U.S. patent application number 14/191951 was filed with the patent office on 2014-06-26 for alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. The applicant listed for this patent is Matthias ECKHARDT, Bradford S. HAMILTON, Frank HIMMELSBACH, Joerg KLEY, Stefan PETERS. Invention is credited to Matthias ECKHARDT, Bradford S. HAMILTON, Frank HIMMELSBACH, Joerg KLEY, Stefan PETERS.
Application Number | 20140179669 14/191951 |
Document ID | / |
Family ID | 41319098 |
Filed Date | 2014-06-26 |
United States Patent
Application |
20140179669 |
Kind Code |
A1 |
PETERS; Stefan ; et
al. |
June 26, 2014 |
Alicyclic carboxylic acid derivatives of benzomorphans and related
scaffolds, medicaments containing such compounds and their use
Abstract
The present invention relates to compounds defined by formula I
##STR00001## wherein the groups A, B, X, m, n and o are defined as
in claim 1, possessing valuable pharmacological activity.
Particularly the compounds are inhibitors of
11.beta.-hydroxysteroid dehydrogenase (HSD) 1 and thus are suitable
for treatment and prevention of diseases which can be influenced by
inhibition of this enzyme, such as metabolic diseases, in
particular diabetes type 2, obesity and dyslipidemia.
Inventors: |
PETERS; Stefan; (Biberach an
der Riss, DE) ; ECKHARDT; Matthias; (Biberach an der
Riss, DE) ; HAMILTON; Bradford S.; (Biberach an der
Riss, DE) ; HIMMELSBACH; Frank; (Mittelbiberach,
DE) ; KLEY; Joerg; (Mittelbiberach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PETERS; Stefan
ECKHARDT; Matthias
HAMILTON; Bradford S.
HIMMELSBACH; Frank
KLEY; Joerg |
Biberach an der Riss
Biberach an der Riss
Biberach an der Riss
Mittelbiberach
Mittelbiberach |
|
DE
DE
DE
DE
DE |
|
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim am Rhein
DE
|
Family ID: |
41319098 |
Appl. No.: |
14/191951 |
Filed: |
February 27, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12991722 |
Jan 5, 2011 |
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PCT/EP2009/055687 |
May 12, 2009 |
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14191951 |
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Current U.S.
Class: |
514/210.18 ;
514/250; 514/286; 514/295; 544/343; 546/63; 546/97 |
Current CPC
Class: |
C07D 491/18 20130101;
A61P 3/06 20180101; C07D 401/06 20130101; C07D 405/06 20130101;
C07D 405/12 20130101; C07D 221/22 20130101; C07D 471/18 20130101;
C07D 401/08 20130101; C07D 221/26 20130101; C07D 491/08 20130101;
A61P 3/10 20180101; A61P 3/00 20180101; C07D 401/12 20130101; A61P
43/00 20180101 |
Class at
Publication: |
514/210.18 ;
546/97; 514/295; 546/63; 514/286; 544/343; 514/250 |
International
Class: |
C07D 221/26 20060101
C07D221/26; C07D 401/08 20060101 C07D401/08; C07D 401/06 20060101
C07D401/06; C07D 491/08 20060101 C07D491/08; C07D 401/12 20060101
C07D401/12; C07D 471/18 20060101 C07D471/18; C07D 221/22 20060101
C07D221/22; C07D 405/06 20060101 C07D405/06; C07D 405/12 20060101
C07D405/12 |
Foreign Application Data
Date |
Code |
Application Number |
May 13, 2008 |
EP |
08156122.7 |
Claims
1. A compound of formula I ##STR00462## wherein X denotes CH, m, n,
o independently of each other denote 0, 1, or 2, wherein the
bicyclic azacycloalkene core structure of formula I annelated with
ring A and attached to the carbonyl group is optionally substituted
with 3 to 5 substituents independently of each other selected from
the group consisting of R.sup.11 and R.sup.12, A denotes a benzo
ring, which is optionally substituted with one to four substituents
independently of each other selected from R.sup.1 or wherein 2
adjacent C-atoms are optionally substituted with R.sup.2 and
R.sup.3 and one or two carbon atoms are optionally substituted
independently with substituents selected from R.sup.1; or a pyrido
ring, which is optionally substituted with one to four substituents
independently of each other selected from R.sup.1 or wherein 2
adjacent C-atoms are optionally substituted with R.sup.2 and
R.sup.3 and one carbon atom is optionally substituted with R.sup.1;
or a pyrrolo, furo, thieno, pyridazino, or pyrazino ring wherein
each of said rings is optionally substituted with one or two
substituents, independently of each other selected from R.sup.1 or
wherein 2 adjacent C-atoms of each of said rings are optionally
substituted with R.sup.2 and R.sup.3; or a pyrimido ring, which is
optionally substituted with one or two substituents, independently
of each other selected from R.sup.1, or a pyrazolo, imidazo,
oxazolo, thiazolo, isoxazolo, or isothiazolo ring wherein each of
said rings is optionally substituted with R.sup.1; or a
1,2,3-triazolo ring substituted with R.sup.N; and B denotes a 5- to
8-membered monocylic, 7- to 12-membered spirocyclic, 6- to
12-membered bicyclic, or 9- to 15-membered tricyclic cycloalkyl
group, each of which is optionally saturated or partially
unsaturated, and wherein 1 or 2-CH.sub.2-- groups optionally are
replaced by --NR.sup.N--, and wherein 1 to 4-CH.sub.2-- groups,
which are not directly linked together, optionally are replaced
independently of each other by O, S, carbonyl, or sulfonyl, and
wherein 1 or 2 CH groups optionally are replaced by N, and wherein
each cycloalkyl group mentioned above optionally is substituted
with one or more substituents independently of each other selected
from L.sup.1, and wherein each said cycloalkyl group optionally is
substituted with 1 or 2 substituents independently of each other
selected from L.sup.2, and wherein 2 adjacent C-atoms of each said
cycloalkyl group optionally are substituted with L.sup.3 and
L.sup.4, and wherein 2 adjacent C-atoms of each said cycloalkyl
group optionally are substituted with L.sup.5 and L.sup.6, with the
proviso that two of L.sup.3 to L.sup.6 are notattached to the same
carbon atom; R.sup.N independently of each other denotes hydrogen,
C.sub.1-6-alkyl, C.sub.3-6-alkenyl, C.sub.3-6-alkynyl,
C.sub.3-6-cycloalkyl, (het)aryl, C.sub.1-4-alkylcarbonyl,
C.sub.1-4-alkyloxycarbonyl, C.sub.1-4-alkylaminocarbonyl,
di-(C.sub.1-3-alkyl)aminocarbonyl, C.sub.1-4-alkylsulfonyl,
(het)arylcarbonyl, (het)arylaminocarbonyl, or (het)arylsulfonyl,
wherein each alkyl, alkenyl, and alkynyl group optionally is mono-
or polysubstituted with fluorine, and optionally is monosubstitued
with hydroxy, C.sub.1-4-alkoxy, C.sub.1-4-alkylsulfanyl,
C.sub.1-4-alkylsulfinyl, C.sub.1-4-alkylsulfonyl, amino,
C.sub.1-4-alkylamino, di-(C.sub.1-4-alkyl)amino,
C.sub.1-4-alkylcarbonylamino, cyano, carboxy,
C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-4-alkyl)aminocarbonyl, or
(het)aryl, R.sup.1 denotes fluorine, chlorine, bromine, iodine,
cyano, nitro, C.sub.1-4-alkyl, hydroxy, C.sub.1-4-alkyloxy,
C.sub.3-6-alkenyloxy, difluoromethyl, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,
2,2,2-trifluoro-1-hydroxy-1-methylethyl,
2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyloxy,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyloxy, tetrahydrofuran-3-yloxy,
tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranyl-C.sub.1-3-alkyloxy,
tetrahydropyranyl-C.sub.1-3-alkyloxy, (het)aryl, (het)aryloxy,
(het)aryl-C.sub.1-3-alkyl, (het)aryl-C.sub.1-3-alkyloxy,
(het)aryloxy-C.sub.1-3-alkyl, C.sub.1-3-alkyl-carbonyl, (het)
aryl-carbonyl, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,
piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,
3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,
3-oxo-piperazin-1-yl, 4-(C.sub.1-3-alkyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylcarbonyl)-piperazin-1-yl,
4-(C.sub.3-6-cycloalkylcarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkyloxycarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylsulfonyl)-piperazin-1-yl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
C.sub.1-3-alkyl-carbonylamino, (het)aryl-carbonylamino,
(het)aryl-C.sub.1-3-alkyl-carbonyl-amino,
C.sub.1-3-alkyloxy-carbonylamino, aminocarbonylamino,
C.sub.1-3-alkyl-amino-carbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonylamino,
C.sub.1-3-alkyl-sulfonylamino, aminosulfonylamino,
C.sub.1-3-alkylamino-sulfonylamino,
di-(C.sub.1-3-alkyl)-amino-sulfonylamino,
pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonyl amino,
morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonyl amino,
(C.sub.1-3-alkyloxy-carbonylamino)carbonylamino,
(het)arylsulfonylamino, (het)aryl-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-(het)arylcarbonyl amino,
N--(C.sub.1-3-alkyl)-(het) aryl-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N-(aminocarbonyl)-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)aminocarbonyl]-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-(het)arylsulfonylamino,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-sulfonylamino,
oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,
2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl, wherein
the nitrogen atom in position 3 of the aforementioned groups is
optionally substituted with methyl or ethyl,
(hydroxyimino)aminomethyl, (C.sub.1-3-alkyloxyimino)aminomethyl,
carboxy, C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl,
carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyl,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyl,
carboxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyloxy,
cyano-C.sub.1-3-alkyloxy, aminocarbonyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyloxy-C.sub.1-3-alkyl,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl,
pyrrolidin-1-yl-C.sub.1-3-alkyl,
C.sub.i-4-alkylcarbonyl-amino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.i-4-alkylcarbonyl-amino-C.sub.1-3-alkyl,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyl,
piperidin-1-yl-C.sub.1-3-alkyl,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyl,
morpholin-4-yl-C.sub.1-3-alkyl,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyl,
piperazin-1-yl-C.sub.1-3-alkyl,
2-oxo-piperazin-1-yl-C.sub.1-3-alkyl,
3-oxo-piperazin-1-yl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyloxy, C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfanyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfinyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfonyl-C.sub.1-3-alkyloxy,
amino-C.sub.1-3-alkyloxy, C.sub.1-3-alkylamino-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
piperidin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyloxy,
morpholin-4-yl-C.sub.1-3-alkyloxy,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyloxy,
piperazin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-piperazin-1-yl-C.sub.1-3-alkyloxy,
3-oxo-piperazin-1-yl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkylsulfinyl,
C.sub.1-3-alkylsulfonyl, C.sub.1-3-alkylsulfonyloxy,
(het)arylsulfonyl, (het)arylsulfonyloxy, trifluoromethylsulfanyl,
trifluoromethylsulfinyl, trifluoromethylsulfonyl, aminosulfonyl,
C.sub.1-3-alkyl-aminosulfonyl, di-(C.sub.1-3-alkyl)-aminosulfonyl,
pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,
morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl, or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonyl, wherein the
above-mentioned saturated heterocycles and cycloalkyl-rings are
optionally substituted with one or two groups selected
independently from fluorine, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, and hydroxy, R.sup.2, R.sup.3 are
linked to each other to form a methylenedioxy, ethylenedioxy or
C.sub.3-5-alkylene bridging group, which optionally is mono- or
disubstituted with methyl, and which optionally and independently
is mono- or polyfluorinated; or R.sup.2 and R.sup.3 together, and
combined with the carbon atoms to which they are attached, form a
benzo, pyrido, pyrazino, pyridazino, pyrimido, pyrrolo, furano,
thieno, pyrazolo, imidazo, triazolo, oxazolo, thiazolo, isoxazolo,
or isothiazolo ring, wherein each of said rings optionally is
substituted with one to three substituents, independently of each
other selected from halogen, C.sub.1-3-alkyl, trifluoromethyl,
amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)amino,
C.sub.1-3-alkylcarbonylamino, C.sub.1-3-alkylsulfonylamino,
hydroxy, cyano, carboxy, C.sub.1-3-alkyloxycarbonyl and
C.sub.1-3-alkyloxy, R.sup.10 denotes halogen, C.sub.1-3-alkyl,
difluoromethyl, trifluoromethyl, cyano, nitro, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)amino, acetylamino,
C.sub.1-3-alkylsulfonylamino, carboxy, C.sub.1-4-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,
methylsulfinyl, methylsulfonyl, hydroxy, C.sub.1-3-alkyloxy,
difluoromethoxy, trifluoromethoxy, or phenyl optionally substituted
with 1 or 2 substituents independently of each other selected from
fluorine, methyl, methoxy, cyano, and hydroxy, R.sup.11 denotes
fluorine, C.sub.1-4-alkyl, (het)aryl, hydroxy, C.sub.1-4-alkyloxy,
cyano, carboxy, C.sub.1-4-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylamino-carbonyl, di-(C.sub.1-4-alkyl)-aminocarbonyl,
hydroxy-C.sub.1-4-alkyl or C.sub.1-3-alkyloxy-C.sub.1-4-alkyl,
R.sup.12 denotes fluorine or C.sub.1-4-alkyl, and L.sup.1 denotes
halogen, C.sub.1-4-alkyl, trifluoromethyl, hydroxy,
C.sub.1-4-alkyloxy, or cyano; L.sup.2 denotes fluorine, chlorine,
bromine, iodine, nitro, cyano, hydroxy, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyloxy, tetrahydrofuran-3-yloxy,
tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranyl-C.sub.1-3-alkyloxy,
tetrahydropyranyl-C.sub.1-3-alkyloxy, (het)aryl, (het)aryloxy,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-6-alkyloxy, C.sub.1-6-alkylamino, wherein in each group one
CH.sub.2 group optionally is replaced by carbonyl or sulfonyl, and
wherein each group optionally is mono or polyfluorinated, and
wherein each group optionally is additionally substituted with
hydroxy, chlorine, C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.1-3-alkyloxy, amino, C.sub.1-3-alkyl-amino,
di-(C.sub.1-3-alkyl)-amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,
piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,
3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,
3-oxo-piperazin-1-yl, 4-(C.sub.1-3-alkyl)-piperazin-1-yl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl, carboxy,
C.sub.1-3-alkyloxy-carbonyl, cyano, aminocarbonyl,
C.sub.1-3-alkylamino-carbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl,
C.sub.1-3-alkylcarbonylamino, arylcarbonylamino,
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkylsulfinyl,
C.sub.1-3-alkylsulfonyl, C.sub.3-6-cycloalkyl, (het)aryl, or
(het)aryloxy; or L.sup.2 denotes amino, di-(C.sub.1-3-alkyl)amino,
pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,
2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,
piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylcarbonyl)-piperazin-1-yl,
4-(C.sub.3-6-cycloalkylcarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkyloxycarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylsulfonyl)-piperazin-1-yl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl, (het)aryl-carbonylamino,
C.sub.1-4-alkyloxy-carbonylamino, aminocarbonylamino,
C.sub.1-4-alkyl-aminocarbonylamino, (het)aryl-aminocarbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonylamino,
aminosulfonylamino, C.sub.1-3-alkylamino-sulfonylamino,
di-(C.sub.1-3-alkyl)amino-sulfonylamino,
pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,
morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonylamino,
(C.sub.1-3-alkyloxy-carbonylamino)carbonylamino,
(het)arylsulfonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-(het)arylcarbonylamino,
N--(C.sub.1-3-alkyl)-(het) aryl-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N-(aminocarbonyl)-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)aminocarbonyl]-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3
-alkyl)-(het)arylsulfonylamino,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-sulfonylamino,
carboxy, C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
azetidin-1-yl-carbonyl, pyrrolidin-1-yl-carbonyl,
piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,
piperazin-1-yl-carbonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl,
(het)arylaminocarbonyl,
N--(C.sub.1-3-alkyl)-(het)arylaminocarbonyl,
(het)aryl-C.sub.1-3-alkylaminocarbonyl,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkylaminocarbonyl,
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkysulfinyl, (het)arylsulfonyl,
trifluoromethylsulfanyl, trifluoromethylsulfinyl, aminosulfonyl,
C.sub.1-3-alkyl-aminosulfonyl, di-(C.sub.1-3-alkyl)-aminosulfonyl,
pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,
morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonyl, wherein the saturated
heterocycles and cycloalkyl-rings mentioned in the definition of
L.sup.2 as a single unit or a sub-moiety within another group are
optionally substituted with one or two groups selected from
fluorine, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, and hydroxy, and L.sup.3 and
L.sup.4 are linked to each other and L.sup.5 and L.sup.6 are linked
to each other, such that independently of each other and in each
case together with the 2 adjacent C-atoms to which either L.sup.3
and L.sup.4 or L.sup.5 and L.sup.6 are attached an aryl- or
heteroaryl-group is formed which is fused to the cyclic group B and
which is optionally substituted with 1, 2, or 3 identical or
different groups selected from R.sup.10, while by aryl is meant
phenyl or naphthtyl and by heteroaryl is meant pyrrolyl, furanyl,
thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,
quinolinyl, isoquinolinyl, or pyrrolyl, furanyl, thienyl, and
pyridyl wherein in each 1 or 2 CH groups are replaced by N, or
indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and
isoquinolinyl wherein in each 1 to 3 CH groups are replaced by N,
and where in each >N--H containing heteroaryl all the >N--H
groups present are optionally replaced by other groups
independently selected from >N--R.sup.N, while the (het)aryl
mentioned hereinbefore as a single unit or a sub-moiety within
another group is an aryl group as defined hereinbefore, or a
heteroaryl group as defined hereinbefore, or a ring selected from
the group consisting of 1,2-dihydro-2-oxo-pyridinyl,
1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo-pyridazinyl,
1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,
1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,
1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,
1,2-dihydro-2-oxo-pyrazinyl,
1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, 2,3-dihydro-2-oxo-indolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,
2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,
1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,
1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,
1,4-dihydro-4-oxo-quinazolinyl,
1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,
1,2-dihydro-2-oxoquinoxalinyl,
1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,
1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,
1,2-dihydro-1-oxo-phthalazinyl,
1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,
2,3-dihydro-benzo[1,4]dioxinyl and
3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, wherein each of said rings
is optionally substituted with 1, 2 or 3 substituents independently
of each other selected from R.sup.10, and wherein each >N--H
containing (het)aryl all the >N--H groups present are optionally
replaced by other groups independently selected from
>N--R.sup.N, whilst each of the above-mentioned alkyl or
alkylene moieties may be branched or unbranched, a tautomer,
stereoisomer thereof, mixture thereof, or salt thereof, while the
compounds comprised by the formula II ##STR00463## wherein R is
hydrogen or R'O, while R' is any substituent, M.sup.1 is methyl,
ethyl, propyl, or phenyl, M.sup.2 and M.sup.3 independently of each
other are hydrogen, methyl, ethyl, or hydroxy, and ring B is
C.sub.5-8-cycloalkyl or C.sub.5-8-cycloalkenyl each of which is
optionally substituted with one or more C.sub.1-5-alkyl groups
resulting in B having .ltoreq.10 carbon atoms in total, or
cyclopentyl which is substituted with one methyl group and wherein
one or more carbon atoms are replaced by O, S, N, or
1-(C.sub.1-3-alkoxy)-cyclopent-1-yl,
(C.sub.1-3-alkoxy)-cyclohex-1-yl, 3-hydroxycyclohexyl,
4-hydroxycyclohexyl, 3-acetoxy-cyclohexyl, 4-acetoxy-cyclohexyl,
cyclohexanon-4-yl, tetrahydrofuryl,
1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl,
1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl,
1,2,3,4-tetrahydro-naphthalen-1-yl,
1,2,3,4-tetrahydro-naphthalen-2-yl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]hepta-2,5-dien-7-yl,
1-aza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, or
adamant-1-yl, are excluded.
2. A compound according to claim 1, wherein the sum of m+n+o is 2,
3, or 4.
3. A compound according to claim 1, characterized by a formula
selected from one or more of the formulae I.1 and I.3 to I.9
##STR00464## wherein the bicyclic azacycloalkene core structure of
formulae I.1 and I.3 to I.9 condensed with ring A and attached to
the carbonyl group is optionally substituted with with 3 to 5
substituents independently of each other selected from the group
consisting of R.sup.11 and R.sup.12, and wherein the rings A and B
are defined as in claim 1, R.sup.11 denotes a fluorine atom,
C.sub.1-3-alkyl, phenyl, hydroxy, C.sub.1-3-alkyloxy, cyano,
carboxy, C.sub.1-4-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylamino-carbonyl, di-(C.sub.1-4-alkyl)-aminocarbonyl,
hydroxy-C.sub.1-4-alkyl, or C.sub.1-3-alkyloxy-C.sub.1-4-alkyl,
R.sup.12 denotes a fluorine atom or C.sub.1-3-alkyl, a tautomer,
stereoisomer, mixture thereof, or salt thereof.
4. A compound of formulae I.1-RR or I.1-SS as substructures of
formula I.1 according to claim 3, ##STR00465## wherein the
2,6-methano-azocin core structure with the stereochemical
configuration as depicted is substituted with 3, 4, or 5
substituents, independently of each other selected from the group
consisting of R.sup.11 and R.sup.12, and wherein the rings A, B and
R.sup.11, R.sup.12 are defined as in claim 3, a tautomer,
stereoisomer, mixture thereof, or salt thereof.
5. The compound according to claim 3, wherein the bicyclic
azacycloalkene core structure of formulae I condensed with ring A
and attached to the carbonyl group is mono-substituted with
R.sup.11 and substituted with 2 substituents independently of each
other selected from R.sup.12, while R.sup.11 and R.sup.12 are
defined as in claim 3, a tautomer, stereoisomer, mixture thereof,
or salt thereof.
6. The compound according to claim 1, having the formula:
##STR00466## a tautomer, stereoisomer, mixture thereof, or salt
thereof.
7. (canceled)
8. A physiologically acceptable salt of the compound according to
claim 1 with an inorganic or organic acid or base.
9. A pharmaceutical composition containing a compound according to
claim 1 or a physiologically acceptable salt with an inorganic or
organic acid or base optionally together with one or more inert
carriers and/or diluents.
10. A compound according to claim 1 or a physiologically acceptable
salt with an inorganic or organic acid or base, including the
compounds disclaimed in claim 1, for treatment or prevention of
diseases or conditions which can be influenced by inhibiting the
enzyme 11.beta.-hydroxysteroid dehydrogenase (HSD) 1.
11. A method of using at least one compound according to claim 1 or
a physiologically acceptable salt with an inorganic or organic acid
or base, including the compounds disclaimed in claim 1, for for the
treatment or prevention or diseases or conditions which can be
influenced by inhibiting the enzyme 11.beta.-hydroxysteroid
dehydrogenase (HSD) 1.
12. Process for preparing a compound of formula I according to
claim 1 or a physiologically acceptable salt with an inorganic or
organic acid or base, characterized in that an amine of the formula
III ##STR00467## wherein the groups A, X, m, n, and o are defined
as in claim 1, is reacted with a compound of the formula IV
##STR00468## wherein B is defined as in claim 1, and wherein Y is a
leaving group, and, if necessary any protective group used in the
reactions described above is cleaved concurrently or subsequently;
and optionally the compound of formula I thus obtained is converted
into a physiologically acceptable salt thereof.
Description
[0001] The present invention relates to compounds derived from the
following chemical scaffold which is structurally defined by the
formula I
##STR00002##
wherein the groups A, B, X, m, n, and o are as defined hereinafter,
including the tautomers, the stereoisomers, the mixtures thereof
and the salts thereof. The invention further relates to
pharmaceutical compositions containing a compound of formula I
according to the invention as well as the use of a compound
according to the invention for preparing a pharmaceutical
composition for the treatment of metabolic disorders. In addition,
the invention relates to processes for preparing a pharmaceutical
composition as well as a compound according to the invention.
[0002] In the literature, compounds which have an inhibitory effect
on the enzyme 11.beta.-hydroxysteroid dehydrogenase (HSD) 1 are
proposed for the treatment of the metabolic syndrome, in particular
diabetes type 2, obesity, and dyslipidemia.
[0003] In the scientific publications Acta Poloniae Pharmaceutica
1982, 39, p. 61-64 and Acta Poloniae Pharmaceutica 1987, 39, p.
411-414 the syntheses of the following benzomorphans that may have
various pharmacological activities, particularly analgetic
acitivity, are described:
##STR00003##
[0004] The scientific publication J. Med. Chem. 1979, 22, p.
537-553 describes the synthesis and analgetic activity of a large
number of benzomorphans among which two stereoisomers of the
benzomorphan of the formula
##STR00004##
are mentioned.
[0005] The scientific publication Chem. Ber. 1976, 109, p.
2657-2669 reports the microbiological and chemical transformation
of the benzomorphan of the formula T1 into products of general
formula
##STR00005##
[0006] In the WO 03/097608 opioid and opioid-like compounds of the
general formula R-A-X wherein R, A, and X are as defined therein,
are described for the treatment and prevention of septic shock and
other disorders. Inter alia A denotes a benzomorphan partial
structure of the formula
##STR00006##
[0007] In the U.S. Pat. No. 4,103,857 derivatives of benzomorphans
of the general formula
##STR00007##
wherein R.sup.1, R.sup.2, and Y are as defined therein, are
described as compounds having anticonvulsant, central nervous
system depressant, and diuretic activity. Besides alternative
synthetic routes, the invention describes a principal access to the
compounds of the invention via a route employing N-acylated (Y is
acyl) compounds of the general formula depicted above. The
following N-acylated compounds are explicitly mentioned as
intermediates therein:
##STR00008##
[0008] In the U.S. Pat. No. 4,009,171 derivatives of benzomorphans
of the general formula
##STR00009##
wherein R, Q', X', Y', and Z' are as defined therein, are described
as intermediates for the preparation of benzomorphans that may be
useful as narcotic antagonists. Inter alia Q' has the meaning
cycloalkyl or cycloalkenyl having 3 to 7 ring carbon atoms and
having 3 to 9 total carbon atoms.
[0009] In the DE 28 28 039 derivatives of benzomorphans of the
general formula
##STR00010##
wherein R.sup.1, R.sup.2, and R.sup.3 are as defined therein, are
described as intermediates for the preparation of benzomorphans
that may have analgetic activity. Inter alia the following meanings
of R.sup.3 are defined:
##STR00011##
[0010] In the DE 24 11 382 derivatives of benzomorphans of the
general formula
##STR00012##
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined
therein, are described as intermediates for the preparation of
benzomorphans that have analgetic activity.
[0011] In the DE 24 37 610 derivatives of benzomorphans of the
general formula
##STR00013##
wherein R is hydrogen, methyl, or acetyl and R.sup.1 is methyl or
phenyl, are described as intermediates for the preparation of the
corresponding N-tetrahydrofuran-2-ylmethyl benzomorphans.
[0012] The inventors are not aware that alicyclic carboxylic acid
derivatives of benzomorphans have been described as inhibitors of
11.beta.-hydroxysteroid dehydrogenase (HSD) 1.
AIM OF THE INVENTION
[0013] The aim of the present invention is to find new
benzomorphans or related compounds, particularly those which are
active with regard to the enzyme 11.beta.-hydroxysteroid
dehydrogenase (HSD) 1. A further aim of the present invention is to
discover benzomorphans or related compounds which have an
inhibitory effect on the enzyme 11.beta.-hydroxysteroid
dehydrogenase (HSD) 1 in vitro and/or in vivo and possess suitable
pharmacological and pharmacokinetic properties to use them as
medicaments.
[0014] A further aim of the present invention is to provide new
pharmaceutical compositions which are suitable for the prevention
and/or treatment of metabolic disorders, particularly diabetes and
dyslipidemia.
[0015] Other aims of the present invention will become apparent to
the skilled man directly from the foregoing and following
remarks.
OBJECT OF THE INVENTION
[0016] In a first aspect the present invention relates to compounds
derived from the following chemical scaffold which is structurally
defined by the formula I
##STR00014##
wherein X denotes CH or N, m, n, o independently of each other
denote 0, 1, or 2, wherein the bicyclic azacycloalkene core
structure of general formula I annelated with ring A and attached
to the carbonyl group is optionally substituted with 1, 2, or more
substituents, preferably with 1 to 5, independently of each other
selected from the group consisting of R.sup.11 and R.sup.12, [0017]
A denotes a benzo ring, which is optionally substituted with one to
four substituents independently of each other selected from R.sup.1
or wherein 2 adjacent C-atoms are optionally substituted with
R.sup.2 and R.sup.3 and one or two carbon atoms are optionally
substituted independently with substituents selected from R.sup.1;
or a pyrido ring, which is optionally substituted with one to three
substituents independently of each other selected from R.sup.1 or
wherein 2 adjacent C-atoms are optionally substituted with R.sup.2
and R.sup.3 and one carbon atom is optionally substituted with
R.sup.1; or [0018] a pyrrolo, furo, thieno, pyridazino, or pyrazino
ring wherein each of said rings is optionally substituted with one
or two substituents, independently of each other selected from
R.sup.1 or wherein 2 adjacent C-atoms of each of said rings are
optionally substituted with R.sup.2 and R.sup.3; or [0019] a
pyrimido ring, which is optionally substituted with one or two
substituents, independently of each other selected from R.sup.1; or
[0020] a pyrazolo, imidazo, oxazolo, thiazolo, isoxazolo, or
isothiazolo ring wherein each of said rings is optionally
substituted with R.sup.1; or [0021] a 1,2,3-triazolo ring
substituted with R.sup.N; and [0022] B denotes a 5- to 8-membered
monocylic, 7- to 12-membered spirocyclic, 6- to 12-membered
bicyclic, or 9- to 15-membered tricyclic cycloalkyl group, each of
which is optionally saturated or partially unsaturated, and [0023]
wherein 1 or 2-CH.sub.2-- groups optionally are replaced by
--NR.sup.N--, and [0024] wherein 1 to 4-CH.sub.2-- groups, which
are not directly linked together, optionally are replaced
independently of each other by O, S, carbonyl, or sulfonyl, and
[0025] wherein 1 or 2 CH groups optionally are replaced by N, and
[0026] wherein each cycloalkyl group mentioned above optionally is
substituted with one or more substituents independently of each
other selected from L.sup.1, and wherein each said cycloalkyl group
optionally is substituted with 1 or 2 substituents independently of
each other selected from L.sup.2, and [0027] wherein 2 adjacent
C-atoms of each said cycloalkyl group optionally are substituted
with L.sup.3 and L.sup.4, and [0028] wherein 2 adjacent C-atoms of
each said cycloalkyl group optionally are substituted with L.sup.5
and L.sup.6, with the proviso that two of L.sup.3 to L.sup.6 are
not attached to the same carbon atom; [0029] R.sup.N independently
of each other denotes hydrogen, C.sub.1-6-alkyl, C.sub.3-6-alkenyl,
C.sub.3-6-alkynyl, C.sub.3-6-cycloalkyl, (het)aryl,
C.sub.1-4-alkylcarbonyl, C.sub.1-4-alkyloxycarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)aminocarbonyl,
C.sub.1-4-alkylsulfonyl, (het)arylcarbonyl, (het)arylaminocarbonyl,
or (het)arylsulfonyl, [0030] wherein each alkyl, alkenyl, and
alkynyl group optionally is mono- or polysubstituted with fluorine,
and optionally is monosubstitued with hydroxy, C.sub.1-4-alkoxy,
C.sub.1-4-alkylsulfanyl, C.sub.1-4-alkylsulfinyl,
C.sub.1-4-alkylsulfonyl, amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)amino, C.sub.1-4-alkylcarbonylamino, cyano,
carboxy, C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-4-alkyl)aminocarbonyl, or
(het)aryl, [0031] R.sup.1 denotes fluorine, chlorine, bromine,
iodine, cyano, nitro, C.sub.1-4-alkyl, hydroxy, C.sub.1-4-alkyloxy,
C.sub.3-6-alkenyloxy, difluoromethyl, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,
2,2,2-trifluoro-1-hydroxy-1-methylethyl,
2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyloxy,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyloxy, tetrahydrofuran-3-yloxy,
tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranyl-C.sub.1-3-alkyloxy,
tetrahydropyranyl-C.sub.1-3-alkyloxy, (het)aryl, (het)aryloxy,
(het)aryl-C.sub.1-3-alkyl, (het)aryl-C.sub.1-3-alkyloxy,
(het)aryloxy-C.sub.1-3-alkyl, C.sub.1-3-alkyl-carbonyl,
(het)aryl-carbonyl, [0032] amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,
piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,
3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,
3-oxo-piperazin-1-yl, 4-(C.sub.1-3-alkyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylcarbonyl)-piperazin-1-yl,
4-(C.sub.3-6-cycloalkylcarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkyloxycarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylsulfonyl)-piperazin-1-yl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl, [0033]
C.sub.1-3-alkyl-carbonylamino, (het)aryl-carbonylamino,
(het)aryl-C.sub.1-3-alkyl-carbonylamino,
C.sub.1-3-alkyloxy-carbonylamino, aminocarbonylamino,
C.sub.1-3-alkyl-aminocarbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonylamino,
C.sub.1-3-alkyl-sulfonylamino, aminosulfonylamino,
C.sub.1-3-alkylamino-sulfonylamino,
di-(C.sub.1-3-alkyl)amino-sulfonylamino,
pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,
morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonylamino,
(C.sub.1-3-alkyloxy-carbonylamino)carbonylamino,
(het)arylsulfonylamino, (het)aryl-C.sub.1-3-alkyl-sulfonylamino,
[0034] N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-(het)arylcarbonylamino,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N-(aminocarbonyl)-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)aminocarbonyl]-C.sub.1-3-alkylamino, [0035]
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-(het)arylsulfonylamino,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-sulfonylamino,
[0036] oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,
2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl, wherein
the nitrogen atom in position 3 of the aforementioned groups is
optionally substituted with methyl or ethyl, [0037]
(hydroxyimino)aminomethyl, (C.sub.1-3-alkyloxyimino)aminomethyl,
carboxy, C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl, [0038]
carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyl,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyl, [0039]
carboxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyloxy,
cyano-C.sub.1-3-alkyloxy, aminocarbonyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
[0040] hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyloxy-C.sub.1-3-alkyl,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl,
pyrrolidin-1-yl-C.sub.1-3-alkyl,
C.sub.1-4-alkylcarbonyl-amino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-4-alkylcarbonyl-amino-C.sub.1-3-alkyl,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyl,
piperidin-1-yl-C.sub.1-3-alkyl,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyl,
morpholin-4-yl-C.sub.1-3-alkyl,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyl,
piperazin-1-yl-C.sub.1-3-alkyl,
2-oxo-piperazin-1-yl-C.sub.1-3-alkyl,
3-oxo-piperazin-1-yl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl, [0041]
hydroxy-C.sub.1-3-alkyloxy, C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfanyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfinyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfonyl-C.sub.1-3-alkyloxy,
amino-C.sub.1-3-alkyloxy, C.sub.1-3-alkylamino-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
piperidin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyloxy,
morpholin-4-yl-C.sub.1-3-alkyloxy,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyloxy,
piperazin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-piperazin-1-yl-C.sub.1-3-alkyloxy,
3-oxo-piperazin-1-yl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy, [0042]
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkysulfonyl,
C.sub.1-3-alkylsulfonyl, C.sub.1-3-alkylsulfonyloxy,
(het)arylsulfonyl, (het)arylsulfonyloxy, trifluoromethylsulfanyl,
trifluoromethylsulfinyl, trifluoromethylsulfonyl, [0043]
aminosulfonyl, C.sub.1-3-alkyl-aminosulfonyl,
di-(C.sub.1-3-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,
piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,
piperazin-1-yl-sulfonyl, or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonyl, [0044] wherein the
above-mentioned saturated heterocycles and cycloalkyl-rings are
optionally substituted with one or two groups selected
independently from fluorine, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, and hydroxy, [0045] R.sup.2,
R.sup.3 are linked to each other to form a methylenedioxy,
ethylenedioxy or C.sub.3-5-alkylene bridging group, which
optionally is mono- or disubstituted with methyl, and which
optionally and independently is mono- or polyfluorinated; or [0046]
R.sup.2 and R.sup.3 together, and combined with the carbon atoms to
which they are attached, form a benzo, pyrido, pyrazino,
pyridazino, pyrimido, pyrrolo, furano, thieno, pyrazolo, imidazo,
triazolo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring,
wherein each of said rings optionally is substituted with one or
more substituents, preferably one to three substituents,
independently of each other selected from halogen, C.sub.1-3-alkyl,
trifluoromethyl, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, C.sub.1-3-alkylcarbonylamino,
C.sub.1-3-alkylsulfonylamino, hydroxy, cyano, carboxy,
C.sub.1-3-alkyloxycarbonyl and C.sub.1-3-alkyloxy, [0047] R.sup.10
denotes halogen, C.sub.1-3-alkyl, difluoromethyl, trifluoromethyl,
cyano, nitro, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, acetylamino,
C.sub.1-3-alkylsulfonylamino, carboxy, C.sub.1-4-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,
methylsulfinyl, methylsulfonyl, hydroxy, C.sub.1-3-alkyloxy,
difluoromethoxy, trifluoromethoxy, or phenyl optionally substituted
with 1 or 2 substituents independently of each other selected from
fluorine, methyl, methoxy, cyano, and hydroxy, [0048] R.sup.11
denotes fluorine, C.sub.1-4-alkyl, (het)aryl, hydroxy,
C.sub.1-4-alkyloxy, cyano, carboxy, C.sub.1-4-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-4-alkylamino-carbonyl,
di-(C.sub.1-4-alkyl)-aminocarbonyl, hydroxy-C.sub.1-4-alkyl or
C.sub.1-3-alkyloxy-C.sub.1-4-alkyl, [0049] R.sup.12 denotes
fluorine or C.sub.1-4-alkyl, and [0050] L.sup.1 denotes halogen,
C.sub.1-4-alkyl, trifluoromethyl, hydroxy, C.sub.1-4-alkyloxy, or
cyano; [0051] L.sup.2 denotes fluorine, chlorine, bromine, iodine,
nitro, cyano, hydroxy, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyloxy, tetrahydrofuran-3-yloxy,
tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranyl-C.sub.1-3-alkyloxy,
tetrahydropyranyl-C.sub.1-3-alkyloxy, (het)aryl, (het)aryloxy,
[0052] C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-6-alkyloxy, C.sub.1-6-alkylamino, wherein in each group one
CH.sub.2 group optionally is replaced by carbonyl or sulfonyl, and
wherein each group optionally is mono or polyfluorinated, and
wherein each group optionally is additionally substituted with
[0053] hydroxy, chlorine, C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.1-3-alkyloxy, amino, C.sub.1-3-alkyl-amino,
di-(C.sub.1-3-alkyl)-amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,
piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,
3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,
3-oxo-piperazin-1-yl, 4-(C.sub.1-3-alkyl)-piperazin-1-yl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl, carboxy,
C.sub.1-3-alkyloxy-carbonyl, cyano, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl,
C.sub.1-3-alkylcarbonylamino, arylcarbonylamino,
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkylsulfinyl,
C.sub.1-3-alkylsulfonyl, C.sub.3-6-cycloalkyl, (het)aryl, or
(het)aryloxy; [0054] or L.sup.2 denotes amino,
di-(C.sub.1-3-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,
piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,
3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,
3-oxo-piperazin-1-yl, 4-(C.sub.1-3-alkyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylcarbonyl)-piperazin-1-yl,
4-(C.sub.3-6-cycloalkylcarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkyloxycarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylsulfonyl)-piperazin-1-yl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl, [0055]
(het)aryl-carbonylamino, C.sub.1-4-alkyloxy-carbonylamino,
aminocarbonylamino, C.sub.1-4-alkyl-aminocarbonylamino,
(het)aryl-aminocarbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonylamino,
aminosulfonylamino, C.sub.1-3-alkylamino-sulfonylamino,
di-(C.sub.1-3-alkyl)amino-sulfonylamino,
pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,
morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonylamino,
(C.sub.1-3-alkyloxy-carbonylamino)carbonylamino,
(het)arylsulfonylamino, [0056]
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-(het)arylcarbonylamino, N--
(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N-(aminocarbonyl)-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)aminocarbonyl]-C.sub.1-3-alkylamino, [0057]
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-(het)arylsulfonylamino,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-sulfonylamino,
[0058] carboxy, C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
azetidin-1-yl-carbonyl, pyrrolidin-1-yl-carbonyl,
piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,
piperazin-1-yl-carbonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl,
(het)arylaminocarbonyl,
N--(C.sub.1-3-alkyl)-(het)arylaminocarbonyl,
(het)aryl-C.sub.1-3-alkylaminocarbonyl,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkylaminocarbonyl, [0059]
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkylsulfinyl,
(het)arylsulfonyl, trifluoromethylsulfanyl,
trifluoromethylsulfinyl, [0060] aminosulfonyl,
C.sub.1-3-alkyl-aminosulfonyl, di-(C.sub.1-3-alkyl)-aminosulfonyl,
pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,
morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonyl, [0061] wherein the
saturated heterocycles and cycloalkyl-rings mentioned in the
definition of L.sup.2 as a single unit or a sub-moiety within
another group are optionally substituted with one or two groups
selected from fluorine, C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, and hydroxy, and L.sup.3 and
L.sup.4 are linked to each other and L.sup.5 and L.sup.6 are linked
to each other, such that independently of each other and in each
case together with the 2 adjacent C-atoms to which either L.sup.3
and L.sup.4 or L.sup.5 and L.sup.6 are attached an aryl- or
heteroaryl-group is formed which is fused to the cyclic group B and
which is optionally substituted with 1, 2, or 3 identical or
different groups selected from R.sup.10, while by aryl is meant
phenyl or naphthtyl and by heteroaryl is meant pyrrolyl, furanyl,
thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,
quinolinyl, isoquinolinyl, or pyrrolyl, furanyl, thienyl, and
pyridyl wherein in each 1 or 2 CH groups are replaced by N, or
indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and
isoquinolinyl wherein in each 1 to 3 CH groups are replaced by N,
and where in each >N--H containing heteroaryl all the >N--H
groups present are optionally replaced by other groups
independently selected from >N--R.sup.N, while the (het)aryl
mentioned hereinbefore as a single unit or a sub-moiety within
another group is an aryl group as defined hereinbefore, or a
heteroaryl group as defined hereinbefore, or a ring selected from
the group consisting of 1,2-dihydro-2-oxo-pyridinyl,
1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo-pyridazinyl,
1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,
1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,
1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,
1,2-dihydro-2-oxo-pyrazinyl,
1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, 2,3-dihydro-2-oxo-indolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,
2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,
1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,
1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,
1,4-dihydro-4-oxo-quinazolinyl,
1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,
1,2-dihydro-2-oxoquinoxalinyl,
1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,
1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,
1,2-dihydro-1-oxo-phthalazinyl,
1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,
2,3-dihydro-benzo[1,4]dioxinyl and
3,4-dihydro-3-oxo-2H-benzo-[1,4]oxazinyl, wherein each of said
rings is optionally substituted with 1, 2, or 3 substituents
independently of each other selected from R.sup.10, and where in
each >N--H containing (het)aryl all the >N--H groups present
are optionally replaced by other groups independently selected from
>N--R.sup.N, whilst each of the above-mentioned alkyl or
alkylene moieties may be branched or unbranched, the tautomers, the
stereoisomers thereof, the mixtures thereof, and the salts thereof,
while the compounds comprised by the general formula II
##STR00015##
[0061] wherein R is hydrogen or R'O, while R' is any substituent,
M.sup.1 is methyl, ethyl, propyl, or phenyl, M.sup.2 and M.sup.3
independently of each other are hydrogen, methyl, ethyl, or
hydroxy, and ring B is [0062] C.sub.5-8-cycloalkyl or
C.sub.5-8-cycloalkenyl each of which is optionally substituted with
one or more C.sub.1-5-alkyl groups resulting in B having .ltoreq.10
carbon atoms in total, or cyclopentyl which is substituted with one
methyl group and wherein one or more carbon atoms are replaced by
O, S, N, or [0063] 1-(C.sub.1-3-alkoxy)-cyclopent-1-yl,
1-(C.sub.1-3-alkoxy)-cyclohex-1-yl, 3-hydroxycyclohexyl,
4-hydroxycyclohexyl, 3-acetoxy-cyclohexyl, 4-acetoxy-cyclohexyl,
cyclohexanon-4-yl, tetrahydrofuryl,
1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl,
1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl,
1,2,3,4-tetrahydro-naphthalen-1-yl,
1,2,3,4-tetrahydro-naphthalen-2-yl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]hepta-2,5-dien-7-yl,
1-aza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, or
adamant-1-yl, are excluded.
[0064] The compounds of general formula I according to the
invention and the physiologically acceptable salts thereof have
valuable pharmacological properties, particularly an inhibitory
effect on the enzyme 11.beta.-hydroxysteroid dehydrogenase (HSD)
1.
[0065] A further aspect of the invention also relates to the
physiologically acceptable salts of the compounds of general
formula I according to this invention with inorganic or organic
acids.
[0066] In a further aspect this invention relates to pharmaceutical
compositions, containing at least one compound of general formula I
or a physiologically acceptable salt according to the invention,
optionally together with one or more inert carriers and/or
diluents.
[0067] In a further aspect this invention relates to the compounds
according to general formula I, including the compounds of general
formula II, or the physiologically acceptable salts thereof, for
treatment or prevention of diseases or conditions which can be
influenced by inhibiting the enzyme 11.beta.-hydroxysteroid
dehydrogenase (HSD) 1, such as metabolic disorders.
[0068] In a further aspect this invention relates to the use of at
least one compound according to general formula I, including the
compounds of general formula II, or one of the physiologically
acceptable salts thereof for preparing a pharmaceutical composition
which is suitable for the treatment or prevention of diseases or
conditions which can be influenced by inhibiting the enzyme
11.beta.-hydroxysteroid dehydrogenase (HSD) 1, such as metabolic
disorders.
[0069] In a further aspect the present invention relates to a
process for preparing the compounds of general formula I,
characterized in that
in order to prepare compounds of general formula I which are
defined as hereinbefore and hereinafter, an amine of the general
formula III
##STR00016##
wherein the groups A, X, m, n, and o are defined as hereinbefore
and hereinafter, is reacted with a compound of the general formula
IV
##STR00017##
wherein B is defined as hereinbefore and hereinafter and wherein Y
is a leaving group and in particular denotes [0070] fluorine,
chlorine, bromine, cyano, C.sub.1-4-alkoxy, C.sub.2-4-alkenyloxy,
C.sub.2-4-alkynyloxy, partially or fully fluorinated
C.sub.2-10-alkoxy, C.sub.1-4-alkylsulfanyl, oxyarylotriazol,
oxyheteroarylotriazol, heteroaryl, succinyl-N-oxy,
C.sub.1-4-alkylcarbonyloxy, di-(C.sub.1-4-alkyl)-aminocarbonyloxy,
pyrrolylcarbonyloxy, piperidinylcarbonyloxy,
morpholinyl-carbonyloxy, tri-(C.sub.1-4-alkyl)-carbamimidoyloxy,
N,N,N',N'-tetra-(C.sub.1-4-alkyl)uronyl, N,N'-dicyclohexyluronyl,
di-(C.sub.1-4-alkyloxy)-phosphoryloxy,
di-(di-C.sub.1-4-alkylamino)-phosphoryloxy,
dipyrrolidinophosphoryloxy, aryloxy, arylsulfanyl, heterosulfanyl,
or heteroaryloxy, [0071] while the alkyl, alkenyl, and alkynyl
groups mentioned in the definition of the above groups, either
alone or as part of another group, optionally are mono- or
polysubstituted with fluorine, chlorine, C.sub.1-3-alkyl, and/or
C.sub.1-3-alkoxy, [0072] while the aryl groups mentioned in the
definition of the above groups, either alone or as part of another
group, denote phenyl or naphthyl groups and the heteroaryl groups
mentioned in the definition of the above groups, either alone or as
part of another group, denote pyridinyl, pyrimidinyl, triazinyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, whilst both the aryl
and heteroaryl groups optionally are independently mono- or
polysubstituted with fluorine, chlorine, bromine, C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy, nitro, cyano, and/or di-(C.sub.1-3-alkyl)amino
groups, optionally in the presence of a base such as an amine, e.g.
ethyldiisopropylamine, triethylamine, imidazole, or pyridine, or an
inorganic base, e.g. potassium carbonate or calcium oxide, and/or
an additive such as 4-dimethylaminopyridine or
1-hydroxybenzotriazol; while the reations are preferably conducted
between 0 and 120.degree. C. in solvents or mixture of solvents
that are preferably selected from tetrahydrofuran,
1,2-dimethoxyethane, ether, 1,4-dioxane, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile,
dichloromethane, 1,2-dichloroethane, toluene, benzene, hexanes, and
ethyl acetate, but also aqueous and alcoholic solutions may be
usable for some of the combinations listed above; and, if necessary
any protective group used in the reactions described above is
cleaved concurrently or subsequently; if desired a compound of
general formula I thus obtained is resolved into its stereoisomers;
if desired a compound of general formula I thus obtained is
converted into the salts thereof, particularly for pharmaceutical
use into the physiologically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0073] Unless otherwise stated, the groups, residues, and
substituents, particularly A, B, R.sup.N, R.sup.1, R.sup.2,
R.sup.3, R.sup.10, R.sup.11, R.sup.12, L.sup.1, L.sup.2, L.sup.3,
L.sup.4, L.sup.5, L.sup.6, X, m, n, and o are defined as above and
hereinafter. If residues, substituents, or groups occur several
times in a compound they may have the same or different meanings.
Some preferred meanings of individual scaffolds, groups, and
substituents of the compounds according to the invention will be
given hereinafter.
[0074] The indexes m, n, and o each denote independently of each
other 0, 1, or 2. Preferably m, n, and o are chosen such that the
sum of m+n+o is 2, 3, or 4.
[0075] Preferred embodiments of this invention are described by
each of the formulae I.1 to I.9
##STR00018##
wherein the bicyclic azacycloalkene core structure of general
formulae I.1 to I.9 condensed with ring A and attached to the
carbonyl group is optionally substituted with 1, 2, or more
substituents, preferably with 1 to 5, most preferred 1, 2, or 3
substituents, independently of each other selected from the group
consisting of R.sup.11 and R.sup.12, and wherein the rings A and B
are defined as hereinbefore and hereinafter, their tautomers, their
stereoisomers, mixtures thereof, and the salts thereof, while the
compounds of general formula II as defined above are excluded.
[0076] According to a preferred embodiment of the general formula
I.1 compounds of the invention are described by the formula
I.1-RR
##STR00019##
wherein the 2,6-methano-azocin core structure with the
stereochemical configuration as depicted is optionally substituted
with 1, 2, or more substituents independently of each other
selected from the group consisting of R.sup.11 and R.sup.12, and
wherein the rings A, B and R.sup.11, R.sup.12 are defined as
hereinbefore and hereinafter, their tautomers, their stereoisomers,
mixtures thereof, and the salts thereof.
[0077] According to another preferred embodiment of the general
formula I.1a compounds of the invention are described by the
formula I.1-SS
##STR00020##
wherein the 2,6-methano-azocin core structure with the
stereochemical configuration as depicted is optionally substituted
with 1, 2, or more substituents, preferably 1, 2, 3, 4, or 5
substituents, independently of each other selected from the group
consisting of R.sup.11 and R.sup.12, and wherein the rings A, B and
R.sup.11, R.sup.12 are defined as hereinbefore and hereinafter,
their tautomers, their stereoisomers, mixtures thereof, and the
salts thereof.
[0078] Even more preferred compounds are described by the formulae
I.1 to I.9 and I.1-RR and I.1-SS wherein the bicyclic
azacycloalkene core structure of general formulae I.1 to I.9
condensed with ring A and attached to the carbonyl group is
optionally mono-substituted with R.sup.11 and optionally
substituted with 1, 2, or 3 substituents independently of each
other selected from R.sup.12.
[0079] Further preferred embodiments of the invention are
characterized by the following definitions:
a) Definitions (a.sup.i) for A in the order of preference,
ascending from preferably (a.sup.1) to more preferably (a.sup.2) up
to most preferably (a.sup.3): (a.sup.1): Preferably, the ring A
denotes a benzo ring, which is optionally substituted with one to
three substituents independently of each other selected from
R.sup.1 or wherein 2 adjacent C-atoms are optionally substituted
with R.sup.2 and R.sup.3 and one carbon atom is optionally
substituted with R.sup.1; or a pyrido, pyrrolo, furo, thieno,
pyridazino, or pyrazino ring, wherein each of said rings 2 adjacent
C-atoms are optionally substituted with R.sup.2 and R.sup.3 and/or
any hydrogen atom bound to a carbon atom of said rings optionally
is substituted by a group independently selected from R.sup.1; or a
pyrimido ring which is optionally substituted with one or two
substituents independently of each other selected from R.sup.1; or
a pyrazolo, oxazolo, thiazolo, or imidazo ring each of which is
optionally substituted with R.sup.1. (a.sup.2): More preferably,
the ring A denotes a benzo, pyrrolo, or pyrido ring, wherein each
of said rings is optionally substituted with one or two
substituents, independently of each other selected from R.sup.1,
and wherein 2 adjacent C-atoms of each of said rings are optionally
substituted with R.sup.2 and R.sup.3. (a.sup.3): Most preferably,
the ring A denotes a benzo ring, which is optionally substituted
with one or two substituents, independently of each other selected
from R.sup.1, and wherein 2 adjacent C-atoms are optionally
substituted with R.sup.2 and R.sup.3. b) Definitions (b.sup.i) for
B in the order of preference, ascending from preferably (b.sup.1)
to more preferably (b.sup.2) up to most preferably (b.sup.3):
(b.sup.1): Ring B preferably denotes cyclopentyl, cyclohexyl,
cycloheptyl, or cyclooctyl, each of which optionally is partially
unsaturated, and wherein one or two --CH.sub.2-- groups
independently of each other optionally are replaced by O, S,
carbonyl, or sulfonyl, and wherein one or two --CH.sub.2-- group(s)
optionally are replaced by --NR.sup.N--, bicyclohexyl,
bicycloheptyl, bicyclooctyl, bicyclononyl, bicyclodecyl, or
bicycloundecyl, each of which optionally is partially unsaturated,
and in each of which one or two --CH.sub.2-- groups optionally are
replaced independently of each other by O, S, --NR.sup.N--,
carbonyl, or sulfonyl, and in each of which one CH group optionally
is replaced by N, spiro[2.4]heptyl, spiro[3.4]octyl,
spiro[4.4]nonyl, spiro[4.5]decyl, or spiro[5.5]undecyl, each of
which optionally is partially unsaturated, and in each of which one
or two --CH.sub.2-- groups optionally are replaced independently of
each other by O, S, --NR.sup.N--, carbonyl, or sulfonyl,
tricyclononyl, tricyclodecyl, tricycloundecyl, tricyclododecyl,
tricyclotridecyl, or tricyclotetradecyl, in each of which one or
two --CH.sub.2-- groups optionally are replaced independently of
each other by O, S, NR.sup.N, carbonyl, or sulfonyl, and in each of
which one CH group optionally is replaced by N, wherein each of the
rings B above optionally is substituted with one or more
substituents, preferably 1, 2, 3, or 4 substituents, independently
of each other selected from L.sup.1, and/or wherein each of the
rings B above optionally is substituted with 1 or 2 substituents
independently of each other selected from L.sup.2, and/or wherein 2
adjacent C-atoms of each of the rings B above optionally are
substituted with L.sup.3 and L.sup.4, and/or wherein 2 adjacent
C-atoms of each of the rings B above optionally are substituted
with L.sup.5 and L.sup.6, with the proviso that two of L.sup.3 to
L.sup.6 cannot be attached to the same carbon atom. (b.sup.2): More
preferably, the ring B denotes cyclopentyl, cyclohexyl, or
cycloheptyl, each of which optionally is partially unsaturated, and
wherein one or two --CH.sub.2-- groups independently of each other
optionally are replaced by O, S, carbonyl, or sulfonyl, and wherein
one or two --CH.sub.2-- group(s) optionally are replaced by
--NR.sup.N--, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo-[2.2.2]octyl,
bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl,
bicyclo[3.2.2]nonyl, bicyclo[5.2.1]decyl, bicyclo[4.2.2]decyl,
bicyclo[3.3.2]decyl, each of which is optionally partially
unsaturated, and in each of which one or two --CH.sub.2-- groups
are optionally replaced independently of each other by O, S,
--NR.sup.N--, carbonyl, or sulfonyl, and in each of which one CH
group is optionally replaced by N, adamantyl, in which one
--CH.sub.2-- group may be replaced by O, S, --NR.sup.N--, carbonyl,
or sulfonyl, and in which one CH group is optionally replaced by N,
wherein each of the rings B above is optionally substituted with
one or more, preferably 1, 2, 3, or 4 substituents, independently
of each other selected from L.sup.1, and/or wherein each of the
above rings B optionally is substituted with 1 or 2 substituents
independently of each other selected from L.sup.2, and/or wherein 2
adjacent C-atoms of each of the above rings B optionally are
substituted with L.sup.3 and L.sup.4. (b.sup.3): Most preferably,
the ring B denotes cyclopentyl, cyclohexyl, cycloheptyl,
4-oxo-cyclohexyl, pyrrolidin-2-yl, pyrrolidin-3-yl,
2-oxo-pyrrolidin-3-yl, 5-oxo-pyrrolidin-2-yl,
5-oxo-pyrrolidin-3-yl, piperidin-2-yl, piperidin-2-yl,
piperidin-3-yl, 6-oxo-piperidin-3-yl, 1,4-dioxanyl,
2-aza-bicyclo[3.1.0]hex-1-yl, 2-aza-bicyclo[2.1.1]hex-1-yl,
bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.1]hept-5-en-2-yl,
3-oxo-2-oxa-bicyclo[2.2.1]hept-1-yl, bicyclo[2.2.2]oct-1-yl,
bicyclo[2.2.2]oct-2-yl, adamant-1-yl, or adamant-2-yl, wherein each
of the above rings B optionally is substituted with one or more
substituents, preferably 1, 2, or 3 substituents, independently of
each other selected from L.sup.1, and/or wherein each of the rings
B above optionally is substituted with 1 or 2 substituents
independently of each other selected from L.sup.2, and/or wherein 2
adjacent C-atoms of each of the above rings B optionally are
substituted with L.sup.3 and L.sup.4 and wherein each >N--H
group in the rings B above is replaced by >N--R.sup.N. c)
Definitions (c.sup.i) for R.sup.N in the order of preference,
ascending from preferably (c.sup.1) to more preferably (c.sup.2) up
to most preferably (c.sup.3): (c.sup.1): Preferably, R.sup.N
denotes hydrogen, C.sub.1-6-alkyl, C.sub.3-6-alkenyl,
C.sub.3-6-cycloalkyl, C.sub.1-4-alkyl-carbonyl, phenylcarbonyl,
C.sub.1-4-alkyloxycarbonyl, C.sub.1-3-alkylaminocarbonyl,
phenylaminocarbonyl, phenyl, C.sub.1-4-alkylsulfonyl, or
phenylsulfonyl, wherein each alkyl group and alkyl sub-moiety
optionally is mono- or polysubstituted with fluorine and optionally
monosubstituted with hydroxy, C.sub.1-4-alkoxy,
C.sub.1-4-alkylcarbonylamino, cyano, carboxy,
C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-4-alkyl)aminocarbonyl, or
phenyl, and wherein each phenyl group and phenyl sub-moiety again
optionally is mono- or disubstituted with R.sup.10. (c.sup.2): More
preferably, R.sup.N denotes hydrogen, C.sub.1-6-alkyl,
C.sub.5-6-cycloalkyl, C.sub.1-4-alkylcarbonyl, phenylcarbonyl,
C.sub.1-4-alkyloxycarbonyl, C.sub.1-3-alkylaminocarbonyl,
phenylaminocarbonyl, phenyl, C.sub.1-4-alkylsulfonyl, or
phenylsulfonyl, wherein each alkyl group and alkyl sub-moiety
optionally is mono- or polysubstituted with fluorine and optionally
monosubstitued with hydroxy, C.sub.1-4-alkoxy, cyano, or phenyl,
and wherein each phenyl group and phenyl sub-moiety again
optionally is mono- or disubstituted with R.sup.10. (c.sup.3): Most
preferably, R.sup.N denotes hydrogen, methyl, propyl, isopropyl,
3-methyl-but-1-yl, cyclopentyl, cyanoethyl, benzyl, acetyl,
ethylcarbonyl, propylcarbonyl, benzylcarbonyl, phenylcarbonyl,
teributoxycarbonyl, ethylaminocarbonyl, phenylaminocarbonyl,
phenyl, methylsulfonyl, phenylsulfonyl, or
3-chloro-2-methylphenylsulfonyl. d) definitions (d.sup.i) for
L.sup.1 in the order of preference, ascending from preferably
(d.sup.1) to more preferably (d.sup.2) up to most preferably
(d.sup.3): (d.sup.1): Preferably, substituents L.sup.1 are selected
from the group consisting of fluorine, chlorine, C.sub.1-4-alkyl,
trifluoromethyl, hydroxy, C.sub.1-4-alkoxy, and cyano, (d.sup.2):
more preferably, fluorine, methyl, ethyl, trifluoromethyl, hydroxy,
methoxy, ethoxy, and cyano, (d.sup.3): most preferably, fluorine,
methyl, hydroxy, and methoxy. e) Definitions (e.sup.i) for L.sup.2
in the order of preference, ascending from preferably (e.sup.1) to
more preferably (e.sup.2) up to most preferably (e.sup.3):
(e.sup.1): Preferably, substituents L.sup.2, are selected from the
group consisting of fluorine, chlorine, bromine, cyano, hydroxy,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-4-alkyloxy, difluoromethyl, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyloxy, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyloxy, (het)aryl, (het)aryloxy,
(het)aryl-C.sub.1-3-alkyl, (het)aryl-C.sub.1-3-alkyloxy,
(het)aryloxy-C.sub.1-3-alkyl, amino, C.sub.1-3-alkylamino,
(het)aryl-C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)amino,
pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,
2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,
piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylcarbonyl)-piperazin-1-yl,
4-(C.sub.3-6-cycloalkylcarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkyloxycarbonyl)-piperazin-1-yl,
4-(C.sub.1-4-alkylsulfonyl)-piperazin-1-yl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl,
C.sub.1-3-alkyl-carbonylamino, (het)aryl-carbonylamino,
(het)aryl-C.sub.1-3-alkyl-carbonylamino,
C.sub.1-4-alkyloxy-carbonylamino, aminocarbonylamino,
C.sub.1-4-alkyl-aminocarbonylamino, (het)aryl-aminocarbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonylamino,
C.sub.1-3-alkyl-sulfonylamino, C.sub.3-6-cycloalkylsulfonylamino,
aminosulfonylamino, C.sub.1-3-alkylamino-sulfonylamino,
di-(C.sub.1-3-alkyl)amino-sulfonylamino,
pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,
morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulfonylamino,
(C.sub.1-3-alkyloxy-carbonylamino)carbonylamino,
(het)arylsulfonylamino, (het)aryl-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-(het)arylcarbonylamino,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N-(aminocarbonyl)-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)aminocarbonyl]-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-(het)arylsulfonylamino,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkyl-sulfonylamino,
carboxy, C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
azetidin-1-ylcarbonyl, pyrrolidin-1-yl-carbonyl,
piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,
piperazin-1-yl-carbonyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl,
(het)arylaminocarbonyl,
N--(C.sub.1-3-alkyl)-(het)arylaminocarbonyl,
(het)aryl-C.sub.1-3-alkylamino-carbonyl,
N--(C.sub.1-3-alkyl)-(het)aryl-C.sub.1-3-alkylaminocarbonyl,
C.sub.1-3-alkyl-carbonyl, (het)aryl-carbonyl,
carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyl,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyl,
carboxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyloxy,
cyano-C.sub.1-3-alkyloxy, aminocarbo-nyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyloxy-C.sub.1-3-alkyl,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl,
pyrrolidin-1-yl-C.sub.1-3-alkyl,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyl,
piperidin-1-yl-C.sub.1-3-alkyl,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyl,
morpholin-4-yl-C.sub.1-3-alkyl,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyl,
piperazin-1-yl-C.sub.1-3-alkyl,
2-oxo-piperazin-1-yl-C.sub.1-3-alkyl,
3-oxo-piperazin-1-yl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl,
C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
arylcarbonylamino-C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfanyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfinyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfonyl-C.sub.1-3-alkyloxy,
amino-C.sub.1-3-alkyloxy, C.sub.1-3-alkyl-amino-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
piperidin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyloxy,
morpholin-4-yl-C.sub.1-3-alkyloxy,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyloxy,
piperazin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-piperazin-1-yl-C.sub.1-3-alkyloxy,
3-oxo-piperazin-1-yl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
3-oxo-4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkylsulfinyl,
C.sub.1-3-alkylsulfonyl, (het)arylsulfonyl,
trifluoromethylsulfanyl, trifluoromethylsulfinyl and
trifluoromethylsulfonyl, wherein the saturated heterocycles and
cycloalkyl-rings mentioned hereinbefore as a single unit or a
sub-moiety within another group are optionally substituted with one
or two groups independently of each other selected from
C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, and hydroxy, and wherein the
(het)aryl mentioned hereinbefore as a single unit or a sub-moiety
within another group is phenyl, naphthyl, pyrrolyl, furanyl,
thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,
quinolinyl, isoquinolinyl, or pyrrolyl, furanyl, thienyl, and
pyridyl in each which 1 or 2 CH are replaced by N, or indolyl,
benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl in
each of which 1 to 3 CH are replaced by N, and
wherein these above-mentioned (het)aryl groups are optionally
substituted with one or two R.sup.10 which may be identical or
different. (e.sup.2): More preferably, substituents L.sup.2 are
selected from the group consisting of fluorine, chlorine, bromine,
cyano, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
hydroxy, C.sub.1-4-alkyloxy, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyloxy,
phenyl, phenoxy, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, phenylmethylamino,
C.sub.1-3-alkyl-carbonylamino, phenylmethylcarbonylamino,
phenyl-carbonylamino, C.sub.1-4-alkyloxycarbonylamino,
C.sub.1-4-alkyl-aminocarbonylamino, phenylaminocarbonylamino,
C.sub.1-3-alkyl-sulfonylamino, C.sub.3-6-cycloalkylsulfonylamino,
phenylmethylsulfonylamino, phenylsulfonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-phenylcarbonylamino,
N--(C.sub.1-3-alkyl)-phenylmethylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino, carboxy,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenylmethylaminocarbonyl, phenylaminocarbonyl,
N--(C.sub.1-3-alkyl)-phenylaminocarbonyl, azetidin-1-ylcarbonyl,
pyrrolidin-1-ylcarbonyl, carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
carboxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyloxy,
cyano-C.sub.1-3-alkyloxy, amino-carbonyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyloxy-C.sub.1-3-alkyl,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyloxy, C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
amino-C.sub.1-3-alkyloxy, C.sub.1-3-alkylamino-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfanyl, C.sub.1-3-alkylsulfinyl, and
C.sub.1-3-alkylsulfonyl, wherein the phenyl groups mentioned
hereinbefore as a single unit or a sub-moiety within another group
are optionally substituted with one or two R.sup.10 which may be
identical or different. (e.sup.3): Most preferably, substituents
L.sup.2 are selected from the group consisting of fluorine,
C.sub.1-3-alkyl, trifluoromethyl, hydroxy, C.sub.1-3-alkyloxy,
C.sub.1-3-alkylamino, benzylamino, C.sub.1-3-alkylcarbonylamino,
phenylmethylcarbonylamino, phenylcarbonylamino,
N-methyl-phenylmethylcarbonylamino, N-methyl-phenylcarbonylamino,
C.sub.1-4-alkyloxycarbonylamino, C.sub.1-3-alkylsulfonylamino,
C.sub.3-6-cycloalkylsulfonylamino, phenylmethylsulfonylamino,
phenylsulfonylamino, furan-2-ylsulfonylamino,
thien-2-ylsulfonylamino, pyrazol-4-ylsulfonylamino,
pyrid-3-ylsulfonylamino, C.sub.1-4-alkylaminocarbonylamino,
phenylaminocarbonylamino, carboxy, C.sub.1-3-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl,
di-(C.sub.1-3-alkyl)aminocarbonyl, phenylmethylaminocarbonyl,
phenylaminocarbonyl, N-methyl-phenylmethylaminocarbonyl,
N--C.sub.1-3-alkyl-N-methylaminocarbonyl, azetidin-1-ylcarbonyl,
pyrrolidin-1-ylcarbonyl, hydroxy-C.sub.1-3-alkyl, or phenyl, while
all above-mentioned phenyl groups are optionally mono- or
disubstituted independently with fluorine, methyl, methoxy,
hydroxy, and cyano; particularly L.sup.2 is fluorine, methyl,
n-propyl, isopropyl, trifluoromethyl, hydroxy, methoxy,
isopropylamino, benzylamino, acetylamine, ethylcarbonylamino,
propylcarbonylamino, isopropylcarbonylamino, benzylcarbonylamino,
phenylcarbonylamino, tertbutoxycarbonylamino, methylsulfonylamino,
ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,
cyclopropylsulfonylamino, cyclohexylsulfonylamino,
benzylsulfonylamino, phenylsulfonylamino,
2-methyl-phenylsulfonylamino, 3-methyl-phenylsulfonylamino,
4-methyl-phenylsulfonylamino, 2-methoxy-phenylsulfonylamino,
3-methoxy-phenylsulfonylamino, 4-methoxy-phenylsulfonylamino,
2-fluoro-phenylsulfonylamino, 3-fluoro-phenylsulfonylamino,
2-fluoro-5-methyl-phenylsulfonylamino,
5-fluoro-2-methyl-phenylsulfonylamino,
2,5-dimethyl-phenylsulfonylamino, furan-2-ylsulfonylamino,
2,5-dimethylfuran-3-ylsulfonylamino, thien-2-ylsulfonylamino,
1-methyl-pyrazol-4-ylsulfonylamino, pyrid-3-ylsulfonylamino,
tertbutylaminocarbonylamino, phenylaminocarbonylamino,
N-methyl-benzylcarbonylamino, N-methyl-phenylcarbonylamino,
carboxy, methoxycarbonyl, isopropoxycarbonyl, aminocarbonyl,
methylaminocarbonyl, n-propylaminocarbonyl, benzylaminocarbonyl,
phenylaminocarbonyl, dimethylaminocarbonyl,
N-methyl-N-ethylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl,
N-methyl-N-isopropylaminocarbonyl, azetidin-1-ylcarbonyl,
pyrrolidin-1-ylcarbonyl, hydroxymethyl, 2-hydroxy-prop-2-yl, and
phenyl. f) definitions (f.sup.i) for L.sup.3 and L.sup.4 in the
order of preference, ascending from preferably (f.sup.1) to more
preferably (f.sup.2) up to most preferably (f.sup.4): (f.sup.1):
Preferably, L.sup.3 and L.sup.4, which are linked to each other,
form with the adjacent carbon atoms to which they are attached an
aryl- or heteroaryl-group which is fused to the cyclic group B, and
which is optionally substituted with one to three identical or
different R.sup.10, [0080] while said aryl- or heteroaryl group is
selected from the group consisting of phenyl, pyrrolyl, furanyl,
thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,
quinolinyl, isoquinolinyl, and [0081] pyrrolyl, furanyl, thienyl,
and pyridyl wherein in each of them one --CH.dbd. group is replaced
by --N.dbd., and [0082] indolyl, quinolinyl, and isoquinolinyl
wherein in each of them one or two --CH.dbd. groups are each
replaced by --N.dbd.. (f.sup.2): More preferably, L.sup.3 and
L.sup.4, which are linked to each other, form with the adjacent
carbon atoms to which they are attached an aryl- or
heteroaryl-group which is fused to the cyclic group B, wherein said
fused aryl- or heteroaryl-group is selected from the group
consisting of benzo, pyrido, pyrimido, pyrazino, pyridazino,
pyrrolo, furano, thieno, imidazo, pyrazolo, oxazolo, isoxazolo,
thiazolo, and isothiazolo, each of which is optionally substituted
with one to three identical or different R.sup.10. (f.sup.3): Even
more preferably L.sup.3 and L.sup.4, which are linked to each
other, form with the atoms to which they are linked an aryl- or
heteroaryl-group which is fused to the cyclic group B, wherein said
fused aryl- or heteroaryl-group is selected from the group
consisting of benzo, pyrido, pyrimido, pyrazino, pyridazino,
pyrrolo, furano, thieno, imidazo, pyrazolo, oxazolo, isoxazolo,
thiazolo, and isothiazolo, each of which is optionally substituted
with one to three identical or different R.sup.10. (f.sup.4): Most
preferably L.sup.3 and L.sup.4, which are linked to each other,
form with the adjacent carbon atoms to which they are attached an
aryl- or heteroaryl-group which is fused to the cyclic group B,
wherein said fused aryl- or heteroaryl-group is selected from the
group consisting of benzo, pyrido, pyrimido, pyrrolo, furano,
thieno, imidazo and oxazolo group, each of which is optionally
substituted with 1, 2, or 3 identical or different R.sup.10,
particularly benzo, which is optionally substituted with 1, 2, or 3
identical or different R.sup.10. g) definitions (g.sup.i) for
L.sup.5 and L.sup.6 in the order of preference, ascending from
preferably (g.sup.1) to more preferably (g.sup.2) up to most
preferably (g.sup.3): (g.sup.1): Preferably, L.sup.5 and L.sup.6,
which are linked to each other, form with the adjacent carbon atoms
to which they are attached an aryl- or heteroaryl-group which is
fused to the cyclic group B, wherein said fused aryl- or
heteroaryl-group is selected from the group consisting of benzo,
pyrido, pyrimido, pyrazino, pyridazino, pyrrolo, furano, thieno,
imidazo, pyrazolo, oxazolo, isoxazolo, thiazolo, and isothiazolo,
each of which is optionally substituted with one to three identical
or different R.sup.10, (g.sup.2): more preferably selected from the
group consisting of benzo, pyrido, pyrimido, pyrazino, and
pyridazino, each of which is optionally substituted with one to
three identical or different R.sup.10, (g.sup.3): most preferably
benzo, which is optionally substituted with one to three identical
or different R.sup.10.
[0083] Regarding the definitions of L.sup.3 and L.sup.4 and of
L.sup.5 and L.sup.6 in cases where an N-containing heteroaryl-group
fused to the cyclic group B is formed, and where said N-containing
hetero-aryl-group is substituted with hydroxy at the carbon atom
adjacent to the nitrogen, a tautomeric amide substructure may be
formed and both tautomers are part of the invention. Examples of
substructures of the ring B wherein two adjacent C-atoms are
substituted with L.sup.3 and L.sup.4, wherein a tautomeric amide is
formed are depicted in the following table 1:
TABLE-US-00001 ##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029##
##STR00030## ##STR00031## ##STR00032##
h) definitions (h.sup.i) for R.sup.1 in the order of preference,
ascending from preferably (h.sup.1) to more preferably (h.sup.2) up
to most preferably (h.sup.4): (h.sup.1): Preferably, the
substituent R.sup.1 denotes fluorine, chlorine, cyano,
C.sub.1-4-alkyl, hydroxy, C.sub.1-4-alkyloxy, C.sub.3-5-alkenyloxy,
difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkyloxy,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyloxy, tetrahydrofuran-3-yloxy,
tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranyl-C.sub.1-3-alkyloxy,
tetrahydropyranyl-C.sub.1-3-alkyloxy, (het)aryl, (het)aryloxy,
(het)aryl-C.sub.1-3-alkyl, (het)aryl-C.sub.1-3-alkyloxy,
(het)aryloxy-C.sub.1-3-alkyl, C.sub.1-3-alkyl-carbonyl,
(het)aryl-carbonyl, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,
piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,
3-oxo-morpholin-4-yl, 3-oxo-piperazin-1-yl,
4-(C.sub.1-4-alkylcarbonyl)-piperazin-1-yl,
C.sub.1-3-alkyl-carbonylamino, (het)aryl-carbonylamino,
C.sub.1-3-alkyloxy-carbonylamino,
C.sub.1-3-alkyl-aminocarbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, C.sub.1-3-alkyl-sulfonylamino,
C.sub.1-3-alkylamino-sulfonylamino,
di-(C.sub.1-3-alkyl)amino-sulfonylamino,
pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,
morpholin-4-yl-sulfonylamino, (het)arylsulfonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-(het)arylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N--(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)-aminocarbonyl]-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-(het)arylsulfonylamino,
(hydroxyimino)aminomethyl, (C.sub.1-3-alkyloxyimino)aminomethyl,
carboxy, C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyl,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl,
carboxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyloxy,
cyano-C.sub.1-3-alkyloxy, amino-carbonyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl-oxy,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyloxy-C.sub.1-3-alkyl,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl,
pyrrolidin-1-yl-C.sub.1-3-alkyl,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyl,
C.sub.1-4-alkyl-carbonyl-amino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-4-alkylcarbonyl-amino-C.sub.1-3-alkyl,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyl,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfinyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulfonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyloxy,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyloxy,
morpholin-4-yl-C.sub.1-3-alkyloxy,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyloxy, C.sub.1-3-alkylsulfonyl,
aminosulfonyl, C.sub.1-3-alkyl-aminosulfonyl,
di-(C.sub.1-3-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,
piperidin-1-yl-sulfonyl, or morpholin-4-yl-sulfonyl, wherein the
above-mentioned (het)aryl mentioned hereinbefore as a single unit
or a sub-moiety within another group is defined as described
hereinbefore and hereinafter. (h.sup.2): More preferably, R.sup.1
denotes fluorine, chlorine, cyano, C.sub.1-4-alkyl, hydroxy,
C.sub.1-4-alkyloxy, C.sub.3-4-alkenyloxy, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, C.sub.3-6-cycloalkyloxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy, tetrahydrofuranyl-C.sub.1-3-alkyloxy,
tetrahydropyranyl-C.sub.1-3-alkyloxy, (het)aryl, (het)aryloxy,
(het)aryl-C.sub.1-3-alkyloxy, C.sub.1-3-alkyl-carbonyl, amino,
C.sub.1-3-alkylamino, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl,
morpholin-4-yl, 3-oxo-morpholin-4-yl,
C.sub.1-3-alkyl-carbonylamino, (het)aryl-carbonylamino,
C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N--(C.sub.1-3-alkyl)-(het)arylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulfonylamino,
N--(C.sub.1-3-alkyl)-(het)arylsulfonylamino, carboxy,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyl,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyloxy,
aminocarbonyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl-oxy,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyloxy-C.sub.1-3-alkyl,
C.sub.1-4-alkylcarbonyl-amino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-4-alkylcarbonyl-amino-C.sub.1-3-alkyl,
2-oxo-pyrrolidin-1-yl-C.sub.1-3-alkyl,
2-oxo-piperidin-1-yl-C.sub.1-3-alkyl,
3-oxo-morpholin-4-yl-C.sub.1-3-alkyl, hydroxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy, C.sub.1-3-alkylsulfonyl,
aminosulfonyl, C.sub.1-3-alkyl-aminosulfonyl, or
di-(C.sub.1-3-alkyl)-aminosulfonyl, wherein the above-mentioned
(het)aryl groups mentioned hereinbefore as a single unit or a
sub-moiety within another group are selected from the group
consisting of phenyl, furanyl, thienyl, oxazolyl, thiazolyl,
isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and
triazinyl, wherein each group is optionally mono- or disubstituted
with identical or different R.sup.10. (h.sup.3): Even more
preferably, R.sup.1 denotes fluorine, chlorine, C.sub.1-4-alkyl,
hydroxy, C.sub.1-3-alkyloxy, allyloxy, amino,
C.sub.1-3-alkyl-carbonylamino, C.sub.1-3-alkyl-sulfonylamino,
cyano, carboxy, C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkyloxy-C.sub.1-3-alkyl,
C.sub.1-3-alkylcarbonyl-amino-C.sub.1-3-alkyl,
hydroxy-C.sub.1-3-alkyloxy, C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
trifluoromethyl, difluoromethoxy, trifluoromethoxy,
C.sub.1-3-alkylcarbonyl, methylsulfonyl, aminosulfonyl,
C.sub.1-3-alkyl-aminosulfonyl, di-(C.sub.1-3-alkyl)-aminosulfonyl,
phenyl-C.sub.1-3-alkyloxy, phenoxy or phenyl, wherein each phenyl
mentioned hereinbefore as a single unit or a sub-moiety within
another group is optionally monosubstituted with R.sup.10.
(h.sup.4): Most preferably R.sup.1 denotes fluorine, chlorine,
methyl, hydroxy, methoxy, ethoxy, allyloxy, amino, cyano,
ethoxycarbonyl, acetyl, methylsulfonyl, aminosulfonyl,
methylaminosulfonyl, dimethylaminosulfonyl, 1-hydroxyethyl,
benzyloxy, or phenyl. j) Definitions (j.sup.i) for R.sup.2 and
R.sup.3 in the order of preference, ascending from preferably
(j.sup.1)/(j.sup.4) to more preferably (j.sup.2)/(j.sup.5) up to
most preferably (j.sup.3)/(j.sup.6): (j.sup.1): R.sup.2 and R.sup.3
are linked to each other to form a bridging group preferably
selected from the group consisting of methylenedioxy,
difluoromethylenedioxy, ethylenedioxy and a C.sub.3-5-alkylene
bridging group, (j.sup.2): more preferably consisting of
methylenedioxy, ethylenedioxy, propylene, and butylene, (j.sup.3):
most preferably methylenedioxy and ethylenedioxy. (j.sup.4):
Additionally, R.sup.2 and R.sup.3 optionally form, combined with
the adjacent carbon atoms to which they are attached, a group
preferably selected from the group consisting of a benzo, pyrazino,
pyrazolo, imidazo, oxazolo, thiazolo, isoxazolo, and isothiazolo
ring, wherein each of these rings is optionally substituted with
one or more substituents. The six-membered aromatics, pyrazolo, and
imidazo are optionally preferably substituted with one or two and
the other five-membered aromatics with one substituent,
independently of each other selected from fluorine,
C.sub.1-3-alkyl, trifluoromethyl, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, hydroxyl, and C.sub.1-3-alkyloxy,
preferably independently of each other selected from fluorine,
methyl, trifluoromethyl, methylamino, dimethylamino, hydroxyl, and
methoxy. (j.sup.5): As a more preferred option, R.sup.2 and R.sup.3
combined with the adjacent carbon atoms to which they are attached
form a group selected from a benzo, pyrazino, imidazo, oxazolo, and
thiazolo ring, wherein the six-membered rings and the imidazo ring
are optionally substituted with one or two methyl groups and the
other five-membered rings are optionally substituted with one
methyl group. (j.sup.6): Most preferably, R.sup.2 and R.sup.3
together denote methylenedioxy or, together with the adjacent
carbon atoms to which they are attached, form a benzo, pyrazino, or
imidazo ring.
[0084] In cases where R.sup.2 and R.sup.3 together denote an
N-containing heteroaryl-group fused to the cyclic group A and where
said N-containing heteroaryl-group is substituted with hydroxy at
the carbon atom adjacent to the nitrogen, a tautomeric amide
substructure may be formed and both tautomers are part of the
invention; examples of these substructures are analogous to those
described above for the residue combinations L.sup.3/L.sup.4 and
L.sup.5/L.sup.6.
k) definitions (k.sup.i) for R.sup.10 in the order of preference,
ascending from preferably (k.sup.1) to more preferably (k.sup.2) up
to most preferably (k.sup.3): (k.sup.1): Preferably, substituents
R.sup.10 are selected independently of each other from the group
consisting of fluorine, chlorine, bromine, C.sub.1-3-alkyl,
difluoromethyl, trifluoromethyl, cyano, nitro, amino, acetylamine,
methylsulfonylamino, carboxy, C.sub.1-4-alkyloxycarbonyl,
amino-carbonyl, C.sub.1-3-alkylaminocarbonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,
methylsulfinyl, methylsulfonyl, phenyl, hydroxy,
C.sub.1-3-alkyloxy, difluoromethoxy, and trifluoromethoxy.
(k.sup.2): More preferably, substituents R.sup.10 are selected
independently from fluorine, chlorine, methyl, difluoromethyl,
trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, and
trifluoromethoxy. (k.sup.3): Most preferably, substituents R.sup.10
are selected independently from fluorine, chlorine, and methyl. l)
definitions (l.sup.i) for R.sup.11 in the order of preference,
ascending from preferably (l.sup.1) to more preferably (l.sup.2) up
to most preferably (l.sup.4): (l.sup.1): Preferably substituents
R.sup.11 are selected independently of each other from the group
consisting of fluorine, C.sub.1-3-alkyl, phenyl, hydroxy,
C.sub.1-3-alkyloxy, cyano, carboxy, C.sub.1-4-alkyloxy-carbonyl,
aminocarbonyl, C.sub.1-4-alkylamino-carbonyl,
di-(C.sub.1-4-alkyl)-aminocarbonyl, hydroxy-C.sub.1-4-alkyl, and
C.sub.1-3-alkyloxy-C.sub.1-4-alkyl. (l.sup.2): More preferably,
substituents R.sup.11 are selected independently from fluorine,
C.sub.1-3-alkyl, hydroxy, and C.sub.1-3-alkyloxy. (l.sup.3): Most
preferably, substituents R.sup.11 are selected independently from
methyl, ethyl, propyl, hydroxy, or methoxy, (l.sup.4): particularly
methyl and hydroxy. m) Definitions (m.sup.i) for m comprise the
options m.sup.1 for m=0, m.sup.2 for m=1, and m.sup.3 for m=2, n)
definitions (n.sup.i) for n comprise the options n.sup.1 for n=0,
n.sup.2 for n=1, and n.sup.3 for n=2, o) definitions (o.sup.i) for
o comprise the options o.sup.1 for o=0, o.sup.2 for o=1, and
o.sup.3 for o=2. p) Definitions (p.sup.i) for R.sup.12 in the order
of preference, ascending from preferably (p.sup.1) to more
preferably (p.sup.2): (p.sup.1): Preferably, substituents R.sup.12
are selected independently of each other from the group consisting
of fluorine and C.sub.1-3-alkyl, (p.sup.2): more preferably from
methyl and ethyl. x) Definitions (x.sup.i) for X comprise the
options x.sup.1 for X.dbd.CH and x.sup.2 for X.dbd.N.
[0085] Each a.sup.i, b.sup.i, c.sup.i, d.sup.i, . . . p.sup.i,
x.sup.i represents a characterised, individual embodiment for the
corresponding substituent as described above. So given the above
definitions, preferred individual embodiments of the first aspect
of the invention are fully characterised by the term
(a.sup.ib.sup.ic.sup.id.sup.ie.sup.if.sup.ig.sup.ih.sup.ij.sup.ik.sup.il.-
sup.im.sup.in.sup.io.sup.ip.sup.ix.sup.i) if for each letter i in
this term an individual FIGURE is given. Indices i vary
independently from each other. All individual embodiments described
by the term in brackets with full permutation of indices i,
referring to the above definitions, shall be comprised by the
present invention.
[0086] The following table 2 shows, exemplarily and in the order of
increasing preference from the first line to the last line, such
embodiments E-1 to E-15 of the invention that are considered
preferred. This means that embodiment E-15, represented by the
entries in the last row of table 2 is the most preferred
embodiment:
[0087] Particularly preferred embodiments of this invention are
described by each of the formulae I.1a to I.9a
##STR00033##
TABLE-US-00002 TABLE 2 Preferred embodiments E-1 to E-15 of the
invention A B R.sup.N L.sup.1 L.sup.2 L.sup.3/L.sup.4
L.sup.5/L.sup.6 R.sup.1 R.sup.2/R.sup.3 R.sup.10 R.sup.11 m n o
R.sup.12 X E-1 a.sup.1 b.sup.1 c.sup.1 d.sup.1 e.sup.1 f.sup.1
g.sup.1 h.sup.1 j.sup.1/j.sup.4 k.sup.1 l.sup.1 m.sup.1, m.sup.2,
m.sup.3 n.sup.1, n.sup.2, n.sup.3 o.sup.1, o.sup.2, o.sup.3 p.sup.1
x.sup.1, x.sup.2 E-2 a.sup.1 b.sup.2 c.sup.1 d.sup.1 e.sup.2
f.sup.1 g.sup.1 h.sup.2 j.sup.1/j.sup.4 k.sup.1 l.sup.1 m.sup.1,
m.sup.2, m.sup.3 n.sup.1, n.sup.2, n.sup.3 o.sup.1, o.sup.2,
o.sup.3 p.sup.2 x.sup.1, x.sup.2 E-3 a.sup.2 b.sup.2 c.sup.2
d.sup.2 e.sup.2 f.sup.2 g.sup.2 h.sup.2 j.sup.2/j.sup.5 k.sup.2
l.sup.2 m.sup.1, m.sup.2, m.sup.3 n.sup.1, n.sup.2, n.sup.3
o.sup.1, o.sup.2, o.sup.3 p.sup.2 x.sup.1, x.sup.2 E-4 a.sup.2
b.sup.2 c.sup.2 d.sup.2 e.sup.2 f.sup.2 g.sup.2 h.sup.2
j.sup.2/j.sup.5 k.sup.2 l.sup.2 m.sup.1, m.sup.2, m.sup.3 n.sup.1,
n.sup.2, n.sup.3 o.sup.1, o.sup.2, o.sup.3 p.sup.2 x.sup.1, x.sup.2
E-5 a.sup.3 b.sup.3 c.sup.3 d.sup.3 e.sup.3 f.sup.3 g.sup.3 h.sup.3
j.sup.3/j.sup.6 k.sup.3 l.sup.3 m.sup.1, m.sup.2 n.sup.1, n.sup.2
o.sup.1, o.sup.2 p.sup.2 x.sup.1, x.sup.2 E-6 a.sup.3 b.sup.3
c.sup.3 d.sup.3 e.sup.3 f.sup.4 g.sup.3 h.sup.4 j.sup.3/j.sup.6
k.sup.3 l.sup.4 m.sup.2, m.sup.3 n.sup.2, n.sup.3 o.sup.2, o.sup.3
p.sup.2 x.sup.1, x.sup.2 E-7 a.sup.3 b.sup.3 c.sup.3 d.sup.3
e.sup.3 f.sup.3 g.sup.3 h.sup.3 j.sup.3/j.sup.6 k.sup.3 l.sup.3
m.sup.3 n.sup.2 o.sup.2 p.sup.2 x.sup.1, x.sup.2 E-9 a.sup.3
b.sup.3 c.sup.3 d.sup.3 e.sup.3 f.sup.4 g.sup.3 h.sup.4
j.sup.3/j.sup.6 k.sup.3 l.sup.4 m.sup.1 n.sup.2 o.sup.2 p.sup.2
x.sup.1, x.sup.2 E-10 a.sup.3 b.sup.3 c.sup.3 d.sup.3 e.sup.3
f.sup.4 g.sup.3 h.sup.4 j.sup.3/j.sup.6 k.sup.3 l.sup.4 m.sup.2
n.sup.1 o.sup.2 p.sup.2 x.sup.1, x.sup.2 E-11 a.sup.3 b.sup.3
c.sup.3 d.sup.3 e.sup.3 f.sup.4 g.sup.3 h.sup.4 j.sup.3/j.sup.6
k.sup.3 l.sup.4 m.sup.2 n.sup.1 o.sup.2 p.sup.2 x.sup.1, x.sup.2
E-12 a.sup.3 b.sup.3 c.sup.3 d.sup.3 e.sup.3 f.sup.4 g.sup.3
h.sup.4 j.sup.3/j.sup.6 k.sup.3 l.sup.4 m.sup.2 n.sup.2 o.sup.1
p.sup.2 x.sup.1, x.sup.2 E-13 a.sup.3 b.sup.3 c.sup.3 d.sup.3
e.sup.3 f.sup.4 g.sup.3 h.sup.4 j.sup.3/j.sup.6 k.sup.3 l.sup.4
m.sup.2 n.sup.2 o.sup.3 p.sup.2 x.sup.1, x.sup.2 E-14 a.sup.3
b.sup.3 c.sup.3 d.sup.3 e.sup.3 f.sup.4 g.sup.3 h.sup.4
j.sup.3/j.sup.6 k.sup.3 l.sup.4 m.sup.2 n.sup.2 o.sup.2 p.sup.2
x.sup.2 E-15 a.sup.3 b.sup.3 c.sup.3 d.sup.3 e.sup.3 f.sup.4
g.sup.3 h.sup.4 j.sup.3/j.sup.6 k.sup.3 l.sup.3 m.sup.2 n.sup.2
o.sup.2 p.sup.2 x.sup.1
##STR00034##
[0088] wherein the bicyclic azacycloalkene core structure of
general formulae I.1 to I.9 condensed with ring A and attached to
the carbonyl group is optionally substituted with 1, 2, or more
substituents, preferably with 1 to 5, most preferred 1, 2, or 3
substituents, independently of each other selected from the group
consisting of R.sup.11 and R.sup.12, and
wherein the ring B and R.sup.1, R.sup.2, R.sup.3, R.sup.11,
R.sup.12 are defined as hereinbefore and hereinafter, their
tautomers, their stereoisomers, mixtures thereof, and the salts
thereof, while the compounds of general formula II as defined
hereinbefore are excluded.
[0089] According to a preferred embodiment of the general formula
I.1a compounds of the invention are described by the formula
I.1a-RR
##STR00035##
wherein the 2,6-methano-azocin core structure with the
stereochemical configuration as depicted is optionally substituted
with 1, 2, or more substituents, preferably 1, 2, 3, 4, or 5
substituents, independently of each other selected from the group
consisting of R.sup.11 and R.sup.12, and wherein the ring B and
R.sup.1, R.sup.2, R.sup.3, R.sup.11, R.sup.12 are defined as
hereinbefore and hereinafter, their tautomers, their stereoisomers,
mixtures thereof, and the salts thereof.
[0090] According to another preferred embodiment of the general
formula I.1a compounds of the invention are described by the
formula I.1a-SS
##STR00036##
wherein the 2,6-methano-azocin core structure with the
stereochemical configuration as depicted is optionally substituted
with 1, 2, or more substituents, preferably 1, 2, 3, 4, or 5
substituents, independently of each other selected from the group
consisting of R.sup.11 and R.sup.12, and wherein the ring B and
R.sup.1, R.sup.2, R.sup.3, R.sup.11, R.sup.12 are defined as
hereinbefore and hereinafter, their tautomers, their stereoisomers,
mixtures thereof, and the salts thereof.
[0091] Even more preferred compounds are described by the formulae
I.1a to I.9a and I.1a-RR and I.1a-SS wherein the bicyclic
azacycloalkene core structure of general formulae I.1 to I.9
condensed with ring A and attached to the carbonyl group is
optionally mono-substituted with R.sup.11 and optionally
substituted with 1, 2, or 3 substituents independently of each
other selected from R.sup.12, wherein the ring B and R.sup.1,
R.sup.2, R.sup.3, R.sup.11, R.sup.12 are defined as hereinbefore
and hereinafter, their tautomers, their stereoisomers, mixtures
thereof, and the salts thereof.
TERMS AND DEFINITIONS
[0092] Some terms used above and hereinafter to describe the
compounds according to the invention will now be defined more
closely.
[0093] The term "substituted" as used herein, means that any one or
more hydrogens on the designated atom is replaced with a selection
from the indicated group, provided that the designated atom's
normal valence is not exceeded, and that the substitution results
in a stable compound.
[0094] The term "partially unsaturated" as used herein, means that
in the designated group or moiety 1, 2, or more, preferably 1 or 2,
double bonds are present. Preferably as used herein, the term
"partially unsaturated" does not cover fully unsaturated groups or
moieties.
[0095] The term halogen denotes an atom selected from the group
consisting of F, Cl, Br, and I.
[0096] The term C.sub.1-n-alkyl, wherein n may have a value of 1 to
18, denotes a saturated, branched or unbranched hydrocarbon group
with 1 to n C atoms. Examples of such groups include methyl, ethyl,
n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl,
etc.
[0097] The term C.sub.2-n-alkenyl, wherein n has a value of 3 to 6,
denotes a branched or unbranched hydrocarbon group with 2 to n C
atoms and a C.dbd.C double bond. Examples of such groups include
ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.
[0098] The term C.sub.2-n-alkynyl, wherein n has a value of 3 to 6,
denotes a branched or unbranched hydrocarbon group with 2 to n C
atoms and a C.ident.C triple bond. Examples of such groups include
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,
2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc. Unless otherwise
stated alkynyl groups are connected to the remainder of the
molecule via the C atom in position 1. Therefore terms such as
1-propynyl, 2-propynyl, 1-butynyl, etc. are equivalent to the terms
1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc. This also applies
analogously to C.sub.2-n-alkenyl groups.
[0099] The term C.sub.1-n-alkoxy denotes a C.sub.1-n-alkyl-O group,
wherein C.sub.1-n-alkyl is as hereinbefore defined. Examples of
such groups include methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy,
iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy,
etc.
[0100] The term C.sub.1-n-alkylcarbonyl denotes a
C.sub.1-n-alkyl-C(C.dbd.O) group, wherein C.sub.1-n-alkyl is as
hereinbefore defined. Examples of such groups include
methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,
iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl,
sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,
iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl,
n-hexylcarbonyl, iso-hexylcarbonyl, etc.
[0101] The term C.sub.3-n-cycloalkyl denotes a saturated mono-,
bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples
of such groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl,
bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl,
norcaryl, adamantyl, etc. Preferably the term C.sub.3-7-cycloalkyl
denotes saturated monocyclic groups.
[0102] The term C.sub.5-n-cycloalkenyl denotes a
C.sub.5-n-cycloalkyl group which is as hereinbefore defined and
additionally has at least one C.dbd.C double bond.
[0103] The term C.sub.3-n-cycloalkylcarbonyl denotes a
C.sub.3-n-cycloalkyl-C(C.dbd.O) group wherein C.sub.3-n-cycloalkyl
is as hereinbefore defined.
[0104] The term tri-(C.sub.1-4-alkyl)silyl comprises silyl groups
which have identical or two or three different alkyl groups.
[0105] The term di-(C.sub.1-3-alkyl)amino comprises amino groups
which have identical or two different alkyl groups.
[0106] If groups or residues are optionally substituted, this
applies to any form of the group or residue. For instance, if an
alkyl group is optionally mono- or polyfluorinated this comprises
also alkyl residues which are part of larger groups, e.g. alkyloxy,
alkylcarbonyl, alkoxyalkyl, etc. or if a (het)aryl group is
optionally mono- or polysubstituted with a certain substituent or a
set of substituents this also includes (het)aryl groups which are
part of larger groups, e.g. (het)aryl-C.sub.1-n-alkyl,
(het)aryloxy, (het)aryloxy-C.sub.1-n-alkyl,
(het)aryl-C.sub.1-n-alkyloxy, etc. Accordingly, in cases where, for
instance, R.sup.1 or L.sup.2 have e.g. the meaning (het)aryloxy,
while (het)aryl residues are optionally mono- or polyfluorinated
and (het)aryl denotes inter alia phenyl, the meanings mono-, di-,
tri-, tetra-, and pentafluoro-phenoxy are also comprised. The same
applies to groups or residues in which a CH.sub.2 group may be
replaced by O, S, NR, CO, or SO.sub.2. For instance, a residue
having inter alia the meaning hydroxy-C.sub.1-3-alkyl, in which a
CH.sub.2 group may be replaced by CO, this comprises carboxy,
carboxymethyl, hydroxymethylcarbonyl, carboxyethyl,
hydroxymethylcarbonylmethyl, and hydroxyethyl-carbonyl.
[0107] The compounds according to the invention may be obtained
using methods of synthesis known in principle. Preferably, the
compounds are obtained by the following methods according to the
invention which are described in more detail hereinafter.
[0108] A general strategy to access compounds of the invention is
delineated in Scheme 1; A, X, m, n, and o have the meanings as
defined hereinbefore and hereinafter. The key reaction to assemble
the bicyclic framework is an intramolecular reaction of an amino
functionality with a carboxy group that results in the formation of
an amide linkage. The fusion of the carboxylic acid function and
the amino group may be carried out with or without an additive at
elevated temperatures, preferably between 20 and 200.degree. C.
Additives that remove the water forming during the reaction, such
as molecular sieves or orthoesters, or other additives such as
bases, e.g. hexamethyldisilazides, or boronic acids may facilitate
the reaction. Though, more preferably the reaction is done with a
more reactive entity of the carboxy function such as an acyl
halide, ester, thioester, anhydride, mixed anhydride, or ketene
which may be generated in a separate preceding reaction step or in
situ. Preferred acyl halides or pseudohalides are acyl chloride,
acyl fluoride, and acylcyanide. Preferred esters and thioesters are
derived from e.g. methanol/methylthiol, ethanol/ethylthiol,
2,2,2-trifluoroethanol, phenol/thiophenol, substituted
phenol/thiophenol such as 4-nitrophenol or pentafluorophenol,
hydroxyheteroaryl such as hydroxybenzotriazol,
hydroxypyridotriazol, or hydroxytriazines, or N-hydroxysuccinimide.
Preferred mixed anhydrides are derived from alkylcarboxylic acids,
e.g. pivalic acid, carbonates, e.g. methyl and ethyl carbonate,
carbamates, e.g. N,N-dimethyl carbamate, phosphoric acids, e.g.
dimethylphosphoric acid or (Me.sub.2N).sub.2P(O)OH, or ureas, e.g.
dicyclohexylurea, dimethylurea, or tetramethylurea. Additionally, N
acylated derivatives derived from azaheteroaromatics such as
imidazole, triazole, tetrazole, or pyridine such as e.g.
4-dimethylaminopyridine may be used as well. Some of the more
popular reagents used for the activation of the carboxylic acid
function are N,N'-carbonyldiimidazol, dicyclohexylcarbodiimide,
(benzotriazol-1-yloxy)dipiperidinocarbenium hexafluorophosphate or
tetrafluoroborate, (benzotriazol-1-yloxy)dipyrrolidinocarbenium
hexafluorophosphate or tetrafluoroborate,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide,
POCl.sub.3, SOCl.sub.2, (COCl).sub.2, COCl.sub.2, arylboronic acid,
TiCl.sub.4, (MeO).sub.2POCl, cyanuric chloride,
1-hydroxybenzotriazol, 1-hydroxy-7-azabenzotriazol,
benzoltriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate or tetrafluoroborate,
benzoltriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
or tetrafluoroborate,
(7-aza-benzoltriazol-1-yloxy)tripyrrolidino-phosphonium
hexafluorophosphate or tetrafluoroborate,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate or tetrafluoroborate,
O-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate or tetrafluoroborate. This compilation of
reagents represents only a few possibilities to activate an
carboxylic acid function a host of additional reagents is known and
may be used here as well. The reactive carboxylic acid derivatives
may also serve as intermediates for other acylating reagents also
sufficiently reactive for this transformation. The activation step
and the ensuing amide forming step are often best carried out in
the presence of additional additives such as bases, e.g.
ethyldiisopropylamine, triethylamine, alkali metal carbonate,
pyridine, 4-dimethylamino-pyridine, imidazole, dimethylaluminum
amides, lithium amides, alkali metal cyanide, or alkali metal
hexamethyldisilazide. The reactions are preferably conducted in
organic solvents but may also be carried out in aqueous solvents.
Among the organic solvents ordinarily used are
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidinone, dimethylsulfoxide, tetrahydrofuran, hexane,
ether, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane,
1,2-dichloroethane, toluene, benzene, ethyl acetate, quinoline,
pyridine, or mixtures thereof. The reactions may be carried out at
-80.degree. C. to 220.degree. C., preferably between -10.degree. C.
and 120.degree. C. Subsequently, the lactam group is reduced to
give the secondary amine. This transformation is a well established
reaction that may be carried out, for example, using LiAlH.sub.4,
hydrogen in the presence of a catalyst, NaBH.sub.4 in the presence
of e.g. iodine, LiBH.sub.4, borane, sodium in propanol,
Cl.sub.3SiH, silanes, e.g. Et.sub.3SiH, in the presence of a
transition metal such as rhenium, 9-borabicyclo[3.3.1]nonane
(9-BBN), LiBH.sub.3NMe.sub.2, or Et.sub.3SiH combined with
LiEt.sub.3BH. Solvents such as e.g. tetrahydrofuran, ether,
1,2-dimethoxyethane, 1,4-dioxane, hexane, benzene, toluene,
dichloromethane, alcohols, water, or mixtures thereof may be
employed at -78.degree. C. to 200.degree. C., preferably between
-10.degree. C. and 120.degree. C.; though, in combination with some
reducing reagents only a few of these solvents are usable. This
strategy is well suited for the synthesis of the scaffolds I.1 to
I.9.
##STR00037##
[0109] Another common synthetic route to acquire the compounds of
the invention is summarized in Scheme 2; A, X, m, n, and o have the
meanings as defined hereinbefore and hereinafter. The bicyclic
framework is formed via an intramolecular reductive amination
reaction of a primary amine with a ketone functionality. Reductive
aminations have large precedence in organic chemistry and may be
carried out e.g. using hydrogen in the presence of a transition
metal catalyst such as one derived from Ni, Rh, Pd, or Pt,
borohydride reagents, e.g. sodium borohydride, sodium
cyanoborohydride, or sodium triacetoxyborohydride, zinc in
combination with hydrochloric acid, PhSiH.sub.3 with
Bu.sub.2SnCl.sub.2, B.sub.10H.sub.14, or formic acid or salts
thereof. Some of these reagents are preferably used in combination
with an additive such as acid, e.g. acetic acid or mineral acid.
The reactions are preferably conducted in organic solvents or
aqueous mixtures, e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide,
tetrahydrofuran, hexane, ether, 1,4-dioxane, 1,2-dimethoxyethane,
dichloromethane, 1,2-dichloroethane, toluene, benzene, alcohols,
water, or mixtures thereof. The reactions may be carried out at
-80.degree. C. to 200.degree. C., preferably between -10.degree. C.
and 100.degree. C.
##STR00038##
[0110] The strategy shown in Scheme 3, wherein A, X, m, n, and o
have the meanings as defined hereinbefore and hereinafter, is
another valid approach based on the reductive amination reaction
already delineated in Scheme 2. Reaction conditions described there
may be employed analogously here.
##STR00039##
[0111] Scheme 4, wherein A, X, m, n, and o have the meanings as
defined hereinbefore and hereinafter, shows another approach to
assemble the bicyclic framework. This approach is based on an
intramolecular alkylation of the nitrogen group with an appropriate
electrophile of the side-chain. The nitrogen group may be an amino
group, i.e. R.sup.a denotes e.g. hydrogen, methyl, allyl, benzyl,
or dimethoxybenzyl, or an amide group, i.e. R.sup.a denotes e.g.
methoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl,
tert-butoxycarbonyl, trifluormethyl-carbonyl, acetyl,
2,2,2-trichloroethoxycarbonyl, tolylsulfonyl, phenylsulfonyl,
methoxyphenyl-sulfonyl, nitrophenylsulfonyl,
2,2,2-trichloroethylsulfonyl, or 2-trimethylsilylethylsulfonyl. The
nitrogen function is reacted with an electrophilic C.sub.sp3-center
in the side-chain, i.e. LG in Scheme 4 denotes e.g. chlorine,
bromine, iodine, mesyloxy, tosyloxy, or trifluoromethlysulfonyloxy,
in the presence of a base such as e.g. triethylamine,
ethyldiisopropylamine, diazabicycloundecene, alkali metal
carbonate, alkali metal tert-butoxide, alkali metal
diisopropylamide, butyllithium, or sodium hydride. The stronger
bases among them are preferably used in combination with the amides
in e.g. N-methylpyrrolidinone, dimethylsulfoxide, tetrahydrofuran,
hexane, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene,
tert-butanol, isopropanol, or mixtures thereof at temperatures
between -70 and 100.degree. C., preferably between -30 and
60.degree. C. The milder bases listed are preferably used in
combination with the amines in dichloromethane,
N,N-dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide,
tetrahydrofuran, hexane, ether, 1,4-dioxane, 1,2-dimethoxyethane,
toluene, benzene, methanol, ethanol, tert-butanol, isopropanol,
water, or mixtures thereof at temperatures between 0 and
140.degree. C., preferably between 20 and 120.degree. C. For the
amides the conditions originally reported by Mitsunobu may be used
as well. Accordingly, the side-chain leaving group LG is generated
in situ from the hydroxy group (LG=OH) using a phosphine, e.g.
triphenylphosphine or tributylphosphine, in combination with an
azodicarboxylate, e.g. diethyl azodicarboxylate, diisopropyl
azodicarboxylate, or azodicarboxylic dipiperidide. Suited solvents
may be selected from among N,N-dimethylformamide,
N-methylpyrrolidinone, dichloromethane, tetrahydrofuran, hexane,
ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene, and
mixtures thereof. The reaction is preferably conducted at
temperatures between 0 and 100.degree. C.
[0112] The opposite way around, i.e. LG denotes NHR.sup.a and
NHR.sup.a denotes LG, may be applicable as well. Reaction
conditions are equivalent to the original way around.
##STR00040##
[0113] A further generally applicable approach is based on an
electrophilic aromatic substitution reaction (Scheme 5); A, X, m,
n, and o have the meanings as defined hereinbefore and hereinafter.
Thereby the aromatic part of the molecule reacts with an activated
carbon atom of the azacycle to form the bicyclic framework. The
reactive intermediate bears a (partially) positively charged carbon
atom in the azacycle that may be generated by the addition of a
proton of an acid to an olefinic bond or by the activation of an
appropriately positioned leaving group. A huge number of Bronstedt
and Lewis acids have been described for this classical reaction
that may also be used here. The following enumeration is supposed
to give a few more widely used of them: hydrobromic acid,
hydroiodic acid, hydrochloric acid, sulfuric acid, phosphoric acid,
P.sub.4O.sub.10, trifluoroacetic acid, methanesulfonic acid,
toluenesulfonic acid, trifluormethanesulfonic acid,
Sc(OSO.sub.2CF.sub.3).sub.3, SnCl.sub.4, FeCl.sub.3, AlBr.sub.3,
AlCl.sub.3, SbCl.sub.5, BCl.sub.3, BF.sub.3, ZnCl.sub.2,
montmorillonites, POCl.sub.3, and PCl.sub.5. Depending on the
inclination of the leaving group to be substituted and the
electronic nature of the aromatic a more or less powerful acid
catalyst has to be used. Besides the acid catalysts mentioned
silver salts, e.g. AgOSO.sub.2CF.sub.3, may be useful in the
reactions using halides as leaving group. Preferred solvents are
hydrocarbons such as hexanes or cyclohexane, chlorinated
hydrocarbons such as dichloromethane or 1,2-dichloroethane,
perfluorinated hydrocarbons, nitrobenzene, chlorinated benzenes,
heteroaromatics such as quinoline, dimethoxyethane, 1,4-dioxane,
ether, ionic liquids, or mixtures thereof. The reactions may be
carried out between -10.degree. C. and 220.degree. C., preferably
between 20.degree. C. and 180.degree. C. The reactions may also be
conducted under microwave irradiation.
[0114] This synthetic strategy is particularly suited for the
scaffolds I.1 and I.3 to I.9 bearing an electron rich aromatic.
##STR00041##
[0115] The bicyclic scaffold may also be accessed via the route
delineated in Scheme 6; m has the meaning as defined hereinbefore
and hereinafter and PG and PG' are protective groups such as e.g.
trialkylsilyl for PG and benzyl or methyl for PG'. The cyclization
is realized by the addition of a radical intermediate, generated
from the trichloromethyl group and a chlorine abstracting reagent,
onto the double bond. Suited chlorine abstracting reagents are
Bu.sub.3Sn. and (Me.sub.3SO.sub.3Si. that are formed in situ by a
radical initiator, such as azobisisobutyronitrile or
dibenzoylperoxide, from Bu.sub.3SnH and (Me.sub.3Si).sub.3SiH,
respectively. The reaction is preferably conducted in benzene,
toluene, cyclohexane, or hexanes at elevated temperature. This
approach is reported inter alia in Tetrahedron: Asymmetry 1999, 10,
2399-2410. Elaboration of the bicyclic scaffold to the desired
compounds may be accomplished after reduction of the amide
functionality to the amine and removal of the protecting group at
the right-hand end of the molecule and transformation of the
CH.sub.2C.dbd.O sub-structure in the left-hand part of the molecule
to one of the aromatics described hereinbefore. These
transformations are described hereinbefore and hereinafter and are
known for similar compounds from the organic chemistry literature
(see e.g. Thomas L. Gilchrist, Heterocyclenchemie, VCH, Weinheim,
1995).
##STR00042##
[0116] Besides the strategies presented a host of additional
approaches to construct the bicyclic systems of the present
invention can be envisaged and are also reported in the literature
(see e.g. J. Med. Chem. 1970, 13, 630-634; Chem. Rev. 1977, 77,
1-36; J. Med. Chem. 1979, 22, 537-553; J. Org. Chem. 1984, 49,
4033-4044; J. Med. Chem. 1996, 39, 1956-1966; Heterocycles 1996,
43, 15-22; J. Med. Chem. 2002, 45, 3755-3764; J. Org. Chem. 2006,
71, 2046-2055; and references quoted therein). Therefore, the
preceding strategies are in no way meant to restrict the possible
synthetic pathways to access the compounds of the invention but are
only supposed to show a few routes by way of example.
[0117] The synthetic routes presented may rely on the use of
protecting groups. Suitable protecting groups for the respective
functionalities and their removal have been described hereinbefore
and may be employed analogously (see also: Protecting Groups,
Philip J. Kocienski, 3.sup.rd edition, Georg Thieme Verlag,
Stuttgart, 2004 and references quoted therein).
[0118] Compounds according to the invention obtained by the
synthetic routes described may be subsequently converted into other
compounds of the invention by routine processes applicable for
conversion of functional groups. Examples for subsequent conversion
processes are provided in the following paragraphs.
[0119] If in the process of manufacture according to the invention
a compound of general formula I is obtained which contains an
amino, alkylamino or imino group, this may be converted by
acylation or sulfonylation into a corresponding acyl or sulfonyl
compound of general formula I.
[0120] If a compound of general formula I is obtained which
contains a hydroxy group, this may be converted by acylation or
sulfonylation into a corresponding acyl or sulfonyl compound of
general formula I.
[0121] If a compound of general formula I is obtained which
contains a hydroxy group, this may be converted by alkylation into
a corresponding ether of general formula I.
[0122] If a compound of general formula I is obtained which
contains an amino, alkylamino or imino group, this may be converted
by alkylation or reductive alkylation into a corresponding alkyl
compound of general formula I.
[0123] If a compound of general formula I is obtained which
contains an amino group, this may be converted by reaction with an
isocyanate or carbamoyl chloride into a corresponding urea
derivative of general formula I.
[0124] If a compound of general formula I is obtained which
contains a nitro group, this may be converted by reduction into a
corresponding amino compound.
[0125] If a compound of general formula I is obtained which
contains an imino group, this may be converted by nitrosation and
subsequent reduction into a corresponding N-amino-imino
compound.
[0126] If a compound of general formula I is obtained which
contains a C.sub.1-3-alkyloxycarbonyl group, this may be converted
by cleavage of the ester into the corresponding carboxy
compound.
[0127] If a compound of general formula I is obtained which
contains a carboxy group, this may be converted by esterification
into a corresponding ester of general formula I.
[0128] If a compound of general formula I is obtained which
contains a carboxy or ester group, this may be converted by
reaction with an amine into a corresponding amide of general
formula I.
[0129] If a compound of general formula I is obtained which
contains an aromatic substructure, this may be derivatized with a
chlorine, bromine, or iodine atom or a nitro, sulfonic acid,
chlorosulfonyl, or acyl group to a corresponding compound of
general formula I by an electrophilic substitution reaction.
[0130] If a compound of general formula I is obtained which
contains an aromatic amino group, this may be transformed into a
corresponding cyano, fluoro, chloro, bromo, iodo, hydroxy,
mercapto, or azido compound of general formula I by diazotization
and subsequent replacement of the diazo group with cyanide,
fluoride, chloride, bromide, iodide, hydroxide, alkyl or hydrogen
sulfide, or azide, respectively.
[0131] If a compound of general formula I is obtained which
contains an aromatic amino group, this may be converted into a
corresponding aryl derivatized aromatic compound of general formula
I by diazotization and subsequent replacement of the diazo group
with an appropriate aryl nucleophile mediated by a suited
transition metal species.
[0132] If a compound of general formula I is obtained which
contains an aromatic chloro, bromo, iodo,
trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group, this may
be converted into a corresponding aryl, alkenyl, alkynyl, or alkyl
derivatized compound of general formula I by replacement of the
respective group by aryl, alkenyl, alkynyl, or alkyl using a
transition metal species mediated process.
[0133] If a compound of general formula I is obtained which
contains an aromatic chloro, bromo, iodo,
trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group, this may
be replaced for hydrogen to give a corresponding aromatic compound
of general formula I.
[0134] If a compound of general formula I is obtained which
contains two adjacent heteroatoms that are amino and hydroxy,
amino, or mercapto, these heteroatoms may be linked via a carboxy
carbon atom to form a cyclic amidine, imino ester, or imino
thioester substructure that may be part of an aromatic ring.
[0135] If a compound of general formula I is obtained which
contains a cyano group, this may be converted into an amino alkyl
derivatized compound of general formula I by reduction.
[0136] If a compound of general formula I is obtained which
contains a cyano group, this may be converted into a
N-hydroxycarbamimidoyl group by the treatment with
hydroxylamine.
[0137] If a compound of general formula I is obtained which
contains an N-hydroxycarbamimidoyl group, this may be converted to
an oxadiazole derivatized compound of general formula I by the
treatment with a carboxylic or related group.
[0138] If a compound of general formula I is obtained which
contains an aminocarbonyl group, this may be converted by
dehydration into a corresponding cyano compound of general formula
I.
[0139] If a compound of general formula I is obtained which
contains a keto or aldehydic group, this may be converted by
reduction into a corresponding hydroxyl compound of general formula
I.
[0140] If a compound of general formula I is obtained which
contains a keto or aldehydic group, this may be converted by
reaction with a carbon nucleophile into a corresponding hydroxy
alkyl compound of general formula I.
[0141] If a compound of general formula I is obtained which
contains a cyano group, this may be converted into a corresponding
tetrazolyl compound of general formula I by reacting with an azide
salt or derivative.
[0142] If a compound of general formula I is obtained which
contains a keto or an aldehydic group, this may be converted by
reaction with a carbon nucleophile into a corresponding hydroxy
alkyl compound of general formula I.
[0143] If a compound of general formula I is obtained which
contains a keto or aldehydic group, this may be converted by
reduction into a corresponding hydroxyl compound of general formula
I.
[0144] The subsequent esterification is optionally carried out in a
solvent or mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or 1,4-dioxane or
particularly advantageously in the corresponding alcohol optionally
in the presence of an acid such as hydrochloric acid or in the
presence of a dehydrating agent. Isobutyl chloroformate, thionyl
chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic
acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus
pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbo-diimide/N-hydroxysuccinimide,
N,N'-carbonyldiimidazole, triphenylphosphine/carbon tetrachloride,
or combinations thereof optionally in the presence of
4-dimethylamino-pyridine and/or 1-hydroxy-benzotriazole are among
the routinely used reagents to accomplish this transformation. The
reactions are conducted between 0 and 150.degree. C., preferably
between 0 and 80.degree. C.
[0145] The subsequent ester formation may also be carried out by
reacting a compound which contains a carboxy group with a
corresponding alkyl halide.
[0146] The subsequent acylation or sulfonylation is optionally
carried out in a solvent or mixture of solvents such as methylene
chloride, dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran, or 1,4-dioxane with a
corresponding acyl or sulfonyl derivative optionally in the
presence of a tertiary organic base or in the presence of an
inorganic base or in the presence of a dehydrating agent. Routinely
used agents are e.g. isobutyl chloroformate, thionyl chloride,
trimethylchlorosilane, sulfuric acid, methanesulfonic acid,
p-toluenesulfonic acid, phosphorus trichloride, phosphorus
pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
N,N'-carbonyldiimidazole, triphenylphosphine/carbon tetrachloride,
or combinations thereof that may be employed in the presence of
4-dimethylamino-pyridine and/or 1-hydroxy-benzotriazole at
temperatures between 0 and 150.degree. C., preferably between 0 and
80.degree. C.
[0147] The subsequent alkylation is optionally carried out in a
solvent or mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran, or 1,4-dioxane with an
alkylating agent such as a corresponding halide or sulfonic acid
ester, e.g. methyl iodide, ethyl bromide, dimethylsulfate, or
benzyl chloride, optionally in the presence of a tertiary organic
base or in the presence of an inorganic base at temperatures
between 0 and 150.degree. C., preferably between 0 and 100.degree.
C.
[0148] The subsequent reductive alkylation is carried out with a
corresponding carbonyl compound such as e.g. formaldehyde,
acetaldehyde, propionaldehyde, acetone, or butyraldehyde in the
presence of a complex metal hydride such as sodium borohydride,
lithium borohydride, sodium triacetoxyborohydride, or sodium
cyanoborohydride conveniently at a pH of 6-7 and at ambient
temperature or using hydrogen in the presence of a transition metal
catalyst, e.g. palladium/charcoal at a hydrogen pressure of 1 to 5
bar. Methylation may also be carried out in the presence of formic
acid as reducing agent at elevated temperature, e.g. between 60 and
120.degree. C.
[0149] The subsequent urea formation from an amine is optionally
carried out in a solvent or mixture of solvents such as
dimethylformamide, N-methylpyrrolidinone, toluene, acetonitrile,
dichloromethane, 1,2-dichloroethane, ether, tetrahydrofuran,
1,2-dimethoxyethane, or 1,4-dioxane with an isocyanate or carbamoyl
chloride optionally in the presence of a tertiary organic base,
e.g. triethylamine or ethyldiisopropylamine, or in the presence of
an inorganic base, e.g. potassium carbonate or calcium oxide, at
temperatures between 0 and 180.degree. C., preferably between 5 and
120.degree. C. Additives such as pyridine or
4-dimethylaminopyridine may be beneficial.
[0150] The subsequent reduction of a nitro group is carried out,
for example, with hydrogen and a catalyst such as palladium on
carbon, platinum dioxide, or Raney nickel, or using other reducing
agents such as iron or zinc in the presence of an acid such as
acetic acid.
[0151] The subsequent nitrosation of an imino group followed by
reduction to obtain the N-amino-imino compound is carried out, for
example, with an alkyl nitrite such as isoamyl nitrite to form the
N-nitroso-imino compound that is then reduced to the N-amino-imino
compound using, for example, zinc in the presence of an acid such
as acetic acid.
[0152] The subsequent cleaving of a C.sub.1-3-alkyloxycarbonyl
group to obtain the carboxy group is carried out, for example, by
hydrolysis with an acid such as hydrochloric acid or sulfuric acid
or an alkali metal hydroxide such as lithium hydroxide, sodium
hydroxide, or potassium hydroxide.
[0153] The subsequent amide formation is carried out by reacting a
corresponding reactive carboxylic acid derivative with a
corresponding amine optionally in a solvent or mixture of solvents
such as methylene chloride, dimethylformamide, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or
1,4-dioxane, while the amine used may also serve as solvent,
optionally in the presence of a tertiary organic base or in the
presence of an inorganic base or with a corresponding carboxylic
acid in the presence of a dehydrating agent. Isobutyl
chloroformate, thionyl chloride, trim ethylchlorosilane, phosphorus
trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or
triphenylphos-phine/carbon tetrachloride, or combinations thereof
optionally in the presence of 4-dimethylamino-pyridine at
temperatures between 0 and 150.degree. C., preferably between 0 and
80.degree. C., may be applied to achieve the coupling.
[0154] The subsequent introduction of a chlorine, bromine, or
iodine atom onto an aromatic substructure may be carried out by
reacting the aromatic compound with an appropriate electrophile of
the halogen atom. Suited chlorine and bromine electrophiles may be
e.g. N-halosuccinimide, HOCl, HOBr, tertBuOCl, tertBuOBr, chlorine,
bromine, dibromoisocyanuric acid, pyridinium dichlorobromate,
pyridinium tribromide, or sulfuryl chloride that may be used alone
or in combination with an acid, e.g. hydrochloric acid, hydrobromic
acid, tetrafluoroboric acid, triflic acid, sulfuric acid, or acetic
acid, or a Lewis acid, e.g. iron(III) halide, borontrifluoride
hydrate, borontrifluoride etherate, or aluminum halide. Further
useful combinations may be LiBr and ceric ammonium nitrate, KCl or
KBr with Oxone.RTM., or KBr and sodium perborate. Suited iodine
electrophiles may be generated from iodine combined with an
oxidizing agent such as nitric acid, sulfur trioxide, manganese
dioxide, HI0.sub.3, hydrogen peroxide, sodium periodate,
peroxydisulfates, and Oxone.RTM.. Further suited iodine
electrophiles may be e.g. iodine chloride, dichloroiodates, and
N-iodosuccinimide. These iodine electrophiles may be used without
an additive or in the presence of an acid such as e.g. acetic acid,
trifluoroacetic acid, or sulfuric acid, or a Lewis acid such as
borontrifluoride hydrate, or copper salts. If a nitro group is to
be introduced appropriate nitro electrophiles may be generated
from, for example, nitric acid, acetyl nitrate, ceric ammonium
nitrate, sodium nitrate, N.sub.2O.sub.5, alkyl nitrate, and
nitronium tetrafluoroborate. Some of these reagents may be used
without an additive, though, several of them are better used in
combination with an acid, e.g. sulfuric acid or triflic acid,
acetic anhydride, trifluoroacetic anhydride, Lewis acid, e.g.
ytterbium triflate or iron acetate, P.sub.2O.sub.5, or a base. The
SO.sub.3H group may be introduced by reacting the aromatic compound
with, for example, concentrated sulfuric acid, SO.sub.3,
ClSO.sub.3H, or ClSO.sub.2NMe.sub.2 combined with indium triflate.
Reacting the aromatic compound with ClSO.sub.3H gives the
corresponding chlorosulfonylated derivative that may be hydrolyzed
to the sulfonic acid. Acylating the aromatic part is conducted
using an acyl electrophile that may be generated from the
respective acyl halide, e.g. chloride, or acyl anhydride and a
Lewis acid such as e.g. aluminum halide, diethylaluminum halide,
indium halide, iron(III) halide, tin(IV) halide, borontrifluoride,
titanium(IV) halide, or a Bronsted acid, e.g. sulfuric acid or
triflic acid. The formyl group is best introduced using the
so-called Vilsmeier or Vilsmeier-Haack conditions: dialkylformamide
combined with phosgene, thionyl chloride, POCl.sub.3, or oxalyl
chloride. Preferred solvents for the electrophilic substitutions
described may differ depending on the electrophile employed; in the
following some more generally applicable are mentioned: methylene
chloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene,
ether, fluorinated hydrocarbons, hexanes, quinoline, or
acetonitrile. The temperatures preferably applied range from 0 to
180.degree. C.
[0155] The subsequent replacement of an aromatic amino group is
initiated by diazotization of the amino group using a nitrous acid
or nitrosonium source or equivalent such as a nitrite salt combined
with an acid, e.g. sodium nitrite and hydrochloric acid,
nitrosonium tetrafluoroborate, or an alkylnitrite, e.g.
tert-butylnitrite or iso-amylnitrite. The diazotization is
optionally carried out in methylene chloride, 1,2-dichloroethane,
N,N-dimethylformamide, N-methylpyrrolidinone, benzene, toluene,
chlorobenzene, tetrahydrofuran, water, ethyl acetate, alcohol,
ether, 1,2-dimethoxyethane, 1,4-dioxane, or mixtures thereof at
temperatures between -10.degree. C. and 100.degree. C.
(diazotization of amino groups is detailed in, for example, Angew.
Chem. Int. Ed. 1976, 15, 251). The subsequent displacement of the
diazo group for a cyano group, chlorine, or bromine using cuprous
cyanide, chloride, or bromide, respectively, is known as the
Sandmeyer reaction (see e.g. March's Advanced Organic Chemistry,
Michael B. Smith and Jerry March, John Wiley & Sons Inc., 6.
Ed., New Jersey, 2007 and references quoted therein); the reaction
is optionally conducted between -10.degree. C. and 120.degree. C.
in one of the solvents or mixtures mentioned above. The replacement
of the diazo group for a fluorine atom may be achieved with a
tetrafluoroborate salt or tetrafluoroboric acid and heating to 20
to 160.degree. C.; the reaction is known as the Schiemann reaction.
Iodine may be introduced by treatment of the diazo compound with an
iodide salt, e.g. sodium iodide, preferably using water or an
aqueous solvent mixture at temperatures between 0 and 120.degree.
C. The diazo group is replaced for hydroxy using water or an
aqueous solvent mixture at temperatures between 0 and 180.degree.
C. The reaction usually works without further additives but the
addition of cuprous oxide or strong acid may be advantageous.
Mercapto or alkylmercapto may be introduced via their corresponding
disulfide salts or dialkyldisulfides at temperatures between 0 and
120.degree. C.; depending on the sulfur species used an inert
solvent or aqueous solvent system may be preferred (see e.g. Synth.
Commun. 2001, 31, 1857 and references quoted therein).
[0156] The subsequent replacement of an aromatic amino group by an
aryl group may be carried out via the corresponding diazo compound
obtainable as described above. The reaction with an aryl
nucleophile, preferably an aryl boronic acid, boronic ester,
trifluoroborate, zinc halide, or stannane, is conducted in the
presence of a transition metal species derived from palladium,
nickel, rhodium, copper, or iron, preferably palladium. The active
catalyst may be a complex of the transition metal with ligands such
as e.g. phosphines, phosphites, imdiazole carbenes, imidazolidine
carbenes, dibenzylideneacetone, allyl, or nitriles, an elemental
form of the transition metal such as palladium on carbon or
nanoparticles, or salts such as chloride, bromide, acetate, or
trifluoroacetate. In these reactions the diazo compound is
preferably employed as its tetrafluoroborate salt optionally in
methylene chloride, N,N-dimethylformamide, N-methylpyrrolidinone,
benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohol,
ether, 1,2-dimethoxyethane, 1,4-dioxane, or mixtures thereof at
temperatures between 10.degree. C. and 180.degree. C., preferably
between 20.degree. C. and 140.degree. C.
[0157] The subsequent replacement of an aromatic chloro, bromo,
iodo atom or an aromatic trifluoromethylsulfonyloxy, mesyloxy, or
tosyloxy group for an aryl, alkenyl, alkynyl, or alkyl residue is
preferably mediated by a transition metal species derived from
palladium, nickel, rhodium, copper, or iron. The active catalyst
may be a complex of the transition metal with ligands such as e.g.
phosphines (e.g. tritertbutylphosphine, tricyclohexylphosphine,
substituted biphenyldicyclohexylphosphines, substituted
biphenylditertbutylphosphines, triphenylphosphine,
tritolylphosphine, trifurylphosphine,
1,1'-bis(diphenylphosphino)-ferrocene), phosphites, imdiazole
carbenes, imidazolidine carbenes, dibenzylideneacetone, allyl, or
nitriles, an elemental form of the transition metal such as
palladium on carbon or nanoparticles of iron or palladium, or a
salt such as fluoride, chloride, bromide, acetate, triflate, or
trifluoroacetate. The replacement is preferably conducted with a
trifluoroborate, boronic acid, or boronic ester (Suzuki or
Suzuki-type reaction), zinc halide (Negishi or Negishi-type
reaction), stannane (Stille reaction), silane (Hiyama or
Hiyama-type reaction), magnesium halide (Kumada or Kumada-type
reaction) of the aryl, alkenyl, or alkyl residue to be introduced.
The terminal alkyne is preferably used as it is or as the zinc
acetylide derivative. Depending on the electrophilic and
nucleophilic reaction partners additives such as halide salts, e.g.
lithium chloride, potassium fluoride, tetrabutylammonium fluoride,
hydroxide sources such as potassium hydroxide or potassium
carbonate, silver salts such as silver oxide or triflate, copper
salts such as copper chloride or copper thiophenecarboxylate may be
advantageous or even essential. Copper iodide is a preferred
additive in the coupling with a terminal alkyne group (Sonogashira
reaction). The coupling reactions are optionally conducted in
methylene chloride, N,N-dimethylformamide, N-methylpyrrolidinone,
benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohol,
ether, dimethylsulfoxide, 1,2-dimethoxyethane, 1,4-dioxane, or
mixtures thereof, though, depending on the nucleophile some of them
are less or not suited at all. Preferred temperatures are in the
range from -10.degree. C. to 180.degree. C.
[0158] The subsequent replacement of an aromatic chlorine, bromine,
or iodine atom or an aromatic trifluoromethylsulfonyloxy, mesyloxy,
or tosyloxy group for a hydrogen atom is preferably mediated by a
transition metal species derived from palladium, nickel, platinum,
or rhodium. The active catalyst may be a complex of the transition
metal with ligands, an elemental form, or a salt of the transition
metal as mentioned above. Raney nickel or palladium on carbon are
among the preferred catalyst species. Suited hydrogen sources may
be hydrogen, preferably at pressures of 1 to 5 bar, silanes, e.g.
trialkoxysilane, boranes, hydrides, e.g. alkali metal borohydride,
formic acid, or formates, e.g. ammonium formate. The reactions are
preferably carried out in methylene chloride,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidinone, benzene, toluene, tetrahydrofuran, water,
ethyl acetate, alcohol, ether, 1,2-dimethoxyethane, 1,4-dioxane, or
mixtures thereof at -10.degree. C. to 180.degree. C., more
preferably at 20.degree. C. to 140.degree. C.
[0159] The subsequent cyclization of two adjacent heteroatoms is
optionally conducted with a carboxy equivalent such as nitrile,
carboxylic chloride or fluoride, carboxylic acid, ketene,
carboxylic ester, or carboxylic thioester. The overall
transformation consists of two reaction steps: attachment of the
carboxy equivalent to one of the two heteroatoms followed by
cyclization with the other heteroatom. The first step is an amide
formation with the amino functionality that may be carried out as
described hereinbefore. The ensuing reaction step, cyclization with
the second heteroatom, may be accomplished by heating in the
presence of an acid, e.g. acetic acid, trifluoroacetic acid,
sulfuric acid, or hydrochloric acid, or a base, e.g. sodium
hydroxide, sodium ethoxide, or sodium teributoxide. The use of
dehydrating reagents such as anhydrides, e.g. acetic anhydride,
orthoesters, e.g. trimethylorthoformate, thionylchloride, phosgene,
diphosgene, triphosgene, phosphorous oxychloride, phosphorous
pentachloride, dialkylcarbodiimides, combinations of phosphines,
e.g. triphenylphosphine or trialkylphosphine with dialkyl
azodicarboxylates, bromine, iodine, or 1,2-dihaloethanes, e.g.
1,2-dibromotetrafluoroethane, may be advantageous. The reactions
are preferably carried out in inert solvents or mixtures such as
methylene chloride, 1,2-dichloroethane, benzene, toluene,
tetrahydrofuran, ether, or combinations thereof, though,
cyclization in the presence of an acid or a base may also be
conducted in water or an alcohol, e.g. methanol, ethanol,
isopropanol, or teributanol, or combinations with these solvents.
The reactions are carried out at temperatures between 0.degree. C.
and 200.degree. C., preferably between 20.degree. C. and
140.degree. C.
[0160] The subsequent reduction of a cyano group to obtain an
aminomethyl group is optionally conducted with hydrogen in the
presence of a transition metal species or with a hydride. Suited
transition metals may be derived from palladium, nickel, platinum,
rhodium, or ruthenium such as, for example, palladium on charcoal,
palladium hydroxide, platinum oxide, or Raney nickel that may be
used in solvents such as ethyl acetate, alcohols, e.g. methanol or
ethanol, dichloromethane, tetrahydrofuran, ether, benzene, toluene,
N,N,-dimethylformamide, or N-methylpyrrolidinone at hydrogen
pressures between 1 and 10 bar, preferably between 1 and 5 bar, and
at temperatures between 0 and 180.degree. C., preferably between 20
and 120.degree. C. Additives such as acids, e.g. hydrochloric acid,
methanesulfonic acid, sulfuric acid, or acetic acid, may be
beneficial for the hydrogenation. Appropriate hydride sources may
be selected from e.g. borohydrides, e.g. sodium borohydride,
potassium trisecbutylborohydride, borane, or lithium
triethylborohydride, or alanates, e.g. lithium aluminum hydride or
diisobutylaluminum hydride. Some of these reagents are best used in
combination with nickel chloride or cobalt chloride as sodium
borohydride. These reagents may be used in e.g. tetrahydrofuran,
ether, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane,
1,2-dichloroethane, benzene, or toluene; some are also compatible
with alcoholic solutions. Preferred reaction temperatures range
from -80.degree. C. to 160.degree. C., more preferred from
-40.degree. C. to 80.degree. C.
[0161] The subsequent formation of a N-hydroxycarbamimidoyl group
from a cyano group may be carried out by the treatment of the cyano
compound with hydroxylamine. The reaction is preferably conducted
in aqueous or alcoholic solvents at temperatures between 0.degree.
C. and 140.degree. C.
[0162] The subsequent formation of an oxadiazole from an
N-hydroxycarbamimidoyl is optionally conducted with a carboxy
equivalent such as nitrile, carboxylic chloride or fluoride,
carboxylic acid, ketene, carboxylic ester, or carboxylic thioester.
The transformation is related to the formation of a ring starting
from two adjacent heteroatoms described above and may be carried
out analogously.
[0163] The subsequent formation of a cyano group from an amino
carbonyl group is optionally conducted by using a dehydrating
reagent such as e.g. anhydride, e.g. acetic anhydride,
trifluoroacetic anhydride, or triflic anhydride, phosgene, thionyl
chloride, oxalyl chloride, POCl.sub.3, PCl.sub.5, P.sub.4O.sub.10,
triphenylphosphite, or triphenyl- or trialkylphosphine combined
with tetrachloromethane, 1,2-dibromotetrafluoroethane, or bromine.
The reactions are preferably carried out in dichloromethane,
1,2-dichloroethane, hexanes, ether, 1,4-dioxane, benzene, toluene,
acetonitrile, mixtures thereof, or without a solvent at
temperatures between 0.degree. C. and 140.degree. C. Additives such
as amines, e.g. pyridine or triethylamine, or N,N-dimethylformamide
may be beneficial.
[0164] The subsequent reduction of a keto or an aldehydic group to
obtain a secondary or primary alcohol may be carried out with a
complex metal hydride such as sodium borohydride, lithium
borohydride, lithium triethylborohydride, diisobutylaluminum
hydride, or lithium aluminum hydride. The reductions may be
conducted in e.g. dichloromethane, 1,2-dichloroethane, hexanes,
ether, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide,
N-methylpyrrolidinone, benzene, toluene, alcohols, e.g. methanol,
water, or mixtures thereof, though, not all reducing agents are
compatible with all of these solvents. Preferred temperatures are
between -80.degree. C. and 140.degree. C. depending on the reducing
power of the reagent. Alternatively, hydrogen in the presence of a
transition metal catalyst may be used for the reduction.
[0165] The subsequent addition of a carbon nucleophile to a keto or
an aldehydic group to obtain a tertiary or secondary alcohol may be
carried out with an alkyl or aryl metal compound, preferably with a
lithium or magnesium derivative. The reactions are preferably
conducted in hexanes, ether, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, benzene, toluene, or mixtures thereof between
-80.degree. C. and 50.degree. C.
[0166] The subsequent conversion of a cyano into a tetrazolyl group
may be achieved by reacting the cyanide with sodium azide or
trimethylsilyl azide in e.g. toluene, xylene, cyclohexane,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidinone, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, alcohol, water, or mixtures thereof.
Beneficial additives may be ZnBr.sub.2, Bu.sub.3SnCl, NH.sub.4Cl,
Bu.sub.2SnO, AlCl.sub.3, AlMe.sub.3, HNEt.sub.3Cl, and NEt.sub.3.
The reactions are preferably conducted between 20.degree. C. and
160.degree. C.
[0167] The subsequent addition of a carbon nucleophile to a keto or
an aldehydic group to obtain a tertiary or secondary alcohol may be
carried out with an alkyl or aryl metal compound, preferably with a
lithium or magnesium derivative. The reactions are preferably
conducted in hexanes, ether, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, benzene, toluene, or mixtures thereof between
-80.degree. C. and 50.degree. C.
[0168] The subsequent reduction of a keto or an aldehydic group to
obtain a secondary or primary alcohol may be carried out with a
complex metal hydride such as sodium borohydride, lithium
borohydride, lithium triethylborohydride, diisobutylaluminum
hydride, or lithium aluminum hydride. The reductions may be
conducted in e.g. dichloromethane, 1,2-dichloroethane, hexanes,
ether, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide,
N-methylpyrrolidinone, benzene, toluene, alcohols, e.g. methanol,
water, or mixtures thereof, though, not all reducing agents
mentioned are compatible with all of these solvents. Preferred
temperatures are between -80.degree. C. and 140.degree. C.
depending on the reducing power of the reagent. Alternatively,
hydrogen in the presence of a transition metal catalyst may be used
for the reduction.
[0169] In the reactions described hereinbefore, any reactive group
present such as hydroxy, carboxy, amino, alkylamino, or imino group
may be protected during the reaction by conventional protecting
groups which are cleaved again after the reaction.
[0170] For example, a protecting group for a hydroxy group may be a
trimethylsilyl, tertbutyldimethylsilyl, triisopropylsilyl, acetyl,
pivaloyl, benzoyl, methyl, tert-butyl, allyl, trityl, benzyl,
4-methoxybenzyl, tetrahydropyranyl, methoxymethyl, ethoxymethyl, or
2-trimethylsilylethoxymethyl group,
protecting groups for a carboxy group may be trimethylsilyl,
methyl, ethyl, tertbutyl, allyl, benzyl, or tetrahydropyranyl,
protecting groups for a ketone or aldehyde may be a ketal or
acetal, respectively, e.g. derived from methanol, glycol, or
propane-1,3-diol, protecting groups for an amino, alkylamino, or
imino group may be methyl, formyl, acetyl, trifluoroacetyl,
ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,
methoxy-benzyl, or 2,4-dimethoxybenzyl and for the amino group
additionally phthalyl, and protecting groups for a terminal alkyne
may be trimethylsilyl, trisopropylsilyl, teributyldimethylsilyl, or
2-hydroxy-isopropyl.
[0171] Any acyl protecting group may be cleaved, for example,
hydrolytically in an aqueous solvent, e.g. in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water, or
1,4-dioxane/water, in the presence of an acid such as
trifluoroacetic acid, hydrochloric acid, or sulfuric acid or in the
presence of an alkali metal base such as lithium hydroxide, sodium
hydroxide, or potassium hydroxide or aprotically, e.g. in the
presence of iodotrimethylsilane, at temperatures between 0 and
120.degree. C., preferably between 10 and 100.degree. C. A
trifluoroacetyl group is preferably cleaved by treating with an
acid such as hydrochloric acid, optionally in a solvent such as
acetic acid, at temperatures between 50 and 120.degree. C. or by
treating with sodium hydroxide solution, optionally in an
additional solvent such as tetrahydrofuran or methanol, at
temperatures between 0 and 80.degree. C.
[0172] Any acetal or ketal protecting group used may be cleaved,
for example, hydrolytically in an aqueous solvent, e.g. in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water, or
1,4-dioxane/water, in the presence of an acid such as
trifluoroacetic acid, hydrochloric acid, or sulfuric acid or
aprotically, e.g. in the presence of iodotrimethylsilane, at
temperatures between 0 and 120.degree. C., preferably between 10
and 100.degree. C.
[0173] A trimethylsilyl group is cleaved, for example, in water, an
aqueous solvent mixture or an alcohol, such as methanol or ethanol,
in the presence of a base such as lithium hydroxide, sodium
hydroxide, potassium carbonate, or sodium methoxide.
[0174] Acids such as e.g. hydrochloric acid, trifluoroacetic acid,
or acetic acid may also be suitable. The cleavage usually takes
place at comparatively low temperatures, e.g. between -60 and
60.degree. C. Silyl groups other than trimethylsilyl are
preferentially cleaved in the presence of an acid, e.g.
trifluoroacetic acid, hydrochloric acid, or sulfuric acid, at
temperatures between 0.degree. C. and 100.degree. C. A particularly
suited cleaving method for silyl groups is based on the use of
fluoride salts, e.g. tetrabutylammonium fluoride, hydrogen
fluoride, or potassium fluoride, in organic solvents, such as for
example diethyl ether, tetrahydrofuran, 1,4-dioxane,
dimethoxyethane, toluene, benzene, dichloroethane, or
dichloromethane at temperatures between -20 and 100.degree. C.
[0175] A benzyl, methoxybenzyl, or benzyloxycarbonyl group is
advantageously cleaved hydrogenolytically, e.g. with hydrogen in
the presence of a catalyst such as palladium on carbon, palladium
hydroxide, or platinum oxide in a solvent such as methanol,
ethanol, ethyl acetate, or glacial acetic acid, optionally in the
presence of an acid, such as hydrochloric acid, at temperatures
between 0 and 100.degree. C., preferably between 20 and 60.degree.
C., and at hydrogen pressures of 1 to 7 bar, preferably 3 to 5 bar.
Trimethylsilyl iodide, boron trichloride, or boron trifluoride in
the presence of a scavenger such as anisol, thioanisol, or
pentamethylbenzene may also be used with benzylether derivatives.
An electron-rich benzyl residue, such as methoxybenzyl, may also be
cleaved oxidatively with e.g.
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ceric ammonium
nitrate (CAN) preferably in an alcoholic or aqueous solvent at
temperatures between 10 and 120.degree. C. A 2,4-dimethoxybenzyl
group is preferably cleaved in trifluoroacetic acid in the presence
of a scavenger such as anisole.
[0176] A tertbutyl or tertbutyloxycarbonyl group is preferably
cleaved by treating with an acid such as trifluoroacetic acid,
sulfuric acid, or hydrochloric acid or by treating with
iodotrimethylsilane optionally using a solvent such as methylene
chloride, 1,4-dioxane, methanol, isopropanol, water, or
diethylether.
[0177] A methyl group at an tertiary amine may be cleaved by the
treatment with 1-chloroethyl chloroformate. Hydrobromic acid and
borontribromide are particularly suited for the cleavage of
methylethers.
[0178] The compounds of general formula I may be resolved into
their enantiomers and/or diastereomers, as mentioned before. Thus,
for example, cis/trans mixtures may be resolved into their cis and
trans isomers, and racemic compounds may be separated into their
enantiomers.
[0179] The cis/trans mixtures may be resolved, for example, by
chromatography into the cis and trans isomers thereof. The
compounds of general formula I which occur as racemates may be
separated by methods known per se (cf. Allinger N. L. and Eliel E.
L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience,
1971) into their optical antipodes and diastereomeric mixtures of
compounds of general formula I may be resolved into their
diastereomers by taking advantage of their different
physico-chemical properties using methods known per se, e.g.
chromatography and/or fractional crystallization; if the compounds
obtained thereafter are racemates, they may be resolved into the
enantiomers as mentioned above.
[0180] The racemates are preferably resolved by column
chromatography on chiral phases or by crystallisation from an
optically active solvent or by reacting with an optically active
substance which forms salts or derivatives, such as e.g. esters or
amides, with the racemic compound. Salts may be formed with
enantiopure acids for basic compounds and with enantiopure bases
for acidic compounds. Diastereomeric derivatives are formed with
enantiopure auxiliary compounds such as e.g. acids, their activated
derivatives, or alcohols. Separation of the diastereomeric mixture
of salts or derivatives thus obtained may be achieved by taking
advantage of their different physico-chemical properties, e.g.
differences in solubility; the free antipodes may be released from
the pure diastereomeric salts or derivatives by the action of
suitable agents. Optically active acids in common use for such a
purpose are e.g. the D- and L-forms of tartaric acid,
dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid,
or quinic acid. Optically active alcohols applicable as auxiliary
may be, for example, (+) or (-)-menthol and optically active acyl
groups in amides may be, for example, (+)- or
(-)-menthyloxycarbonyl.
[0181] As mentioned above, the compounds of formula I may be
converted into salts, particularly for pharmaceutical use into the
physiologically acceptable salts with inorganic or organic acids
provided that compound I bears a basic residue. Acids which may be
used for this purpose include for example hydrochloric acid,
hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric
acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid, or maleic acid.
[0182] If the compounds of formula I contain an acidic residue
like, for example, a carboxy group, they may be converted into the
salts thereof with inorganic or organic bases, particularly for
pharmaceutical use into the physiologically acceptable salts
thereof. Suitable bases for this purpose include, for example,
sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium
isopropoxide, magnesium hydroxide, magnesium ethoxide, ammonium
hydroxide, cyclohexylamine, ethanolamine, diethanolamine,
triethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, and
piperazine.
[0183] The compounds according to the invention are advantageously
also obtainable using the methods described in the examples that
follow, which may also be combined for this purpose with methods
known to the skilled man from the literature.
[0184] As already mentioned, the compounds of general formula I
according to the invention and the physiologically acceptable salts
thereof have valuable pharmacological properties, particularly an
inhibitory effect on the enzyme 11.beta.-hydroxysteroid
dehydrogenase (HSD) 1.
[0185] The biological properties of the new compounds may be
investigated as follows:
[0186] In vitro inhibition of 11.beta.-HSD1 by test compounds was
determined with HTRF (Homogeneous Time-Resolved Fluorescence)
technology (cisbio international, France) detecting cortisol
generated from cortisterone by human liver microsomes. Briefly,
compounds were incubated for 1 hour at 37.degree. C. in Tris buffer
(20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH (200 .mu.M) and
cortisone (80 nM). Cortisol generated in the reaction is then
detected with a competitive immunoassay, involving two HTRF
conjugates: cortisol linked to XL665 and anti-cortisol antibody
labeled with Europium cryptate. The incubation period for detection
reaction was typically 2 hours. The amount of cortisol is
determined by reading the time-resolved fluorescence of the wells
(Ex 320/75 nm; Em 615/8.5 nm and 665/7.5 nm). The ratio of the two
emission signals is then calculated (Em665*10000/Em615). Each assay
contained incubations with vehicle controls instead of compound as
controls for non-inhibited cortisol generation (100% CTL; `high
values`) and incubations with carbenoxolone as controls for fully
inhibited enzyme and cortisol background (0% CTL; `low values`).
Each assay also contained a calibration curve with cortisol to
transform the fluorescent data into cortisol concentrations.
Percent inhibition of each compound was determined relative to the
carbenoxolone signal and IC.sub.50 curves were generated.
[0187] The compounds of general formula I according to the
invention may for example have IC.sub.50 values below 10000 nM,
particularly below 1000 nM, most preferably below 100 nM. In the
Table 2 compounds of the invention (specified in Table 3) and their
inhibitory activity determined as described above are compiled.
TABLE-US-00003 TABLE 2 11.beta.- 11.beta.- 11.beta.- 11.beta.- HSD
HSD HSD HSD Ex. IC.sub.50 Ex. IC.sub.50 Ex. IC.sub.50 Ex. IC.sub.50
No. (nM) No. (nM) No. (nM) No. (nM) 1 964 44 175 93 1494 140 101 2
934 45 240 94 36 141 133 3 274 46 954 95 75 142 1938 4 156 47 106
98 1387 143 179 6 692 48 639 99 420 144 250 7 1192 49 186 101 59
145 254 8 847 50 1551 102 501 146 87 9 1509 51 101 100 1349 147 376
10 1767 52 1397 103 878 148 230 11 1347 53 863 104 762 149 91 5
4573 54 2656 106 1518 150 299 12 1510 56 2442 107 1633 151 242 13
4024 59 555 108 221 152 94 14 136 60 760 109 693 154 185 15 109 61
2104 110 2313 155 243 16 1070 62 666 112 1115 156 198 17 809 63 335
113 404 157 168 18 823 64 631 114 2118 158 135 19 421 66 2536 115
214 160 182 20 138 67 388 116 70 161 283 21 86 68 654 117 340 162
333 22 1434 69 6114 118 149 163 491 23 186 71 2375 119 2763 164 77
24 120 72 693 121 5930 165 1233 25 837 73 663 122 5564 166 2451 26
3509 75 6036 125 1572 167 1470 27 3484 76 667 126 2852 168 2371 29
1116 77 571 128 474 169 2061 30 1005 78 5870 129 2173 170 2132 31
1340 82 1485 130 1153 171 2236 34 859 84 1179 131 432 172 2583 35
1289 85 362 132 210 173 1487 37 197 86 67 133 363 174 178 38 106 87
555 134 1699 175 176 39 499 88 316 135 533 176 625 40 61 89 164 136
2076 177 76 41 373 90 255 137 3525 178 798 42 165 91 1545 138 1394
179 205 43 247 92 459 139 2972 181 3804 182 1510 183 338 184 202
185 294 188 695 189 1461 190 1256 191 398 192 789 193 1010 194 1692
195 275 196 252 197 796 198 2230 199 96 200 83 201 149 202 758 203
260 204 69 205 74 206 86 207 1437 208 40
[0188] In view of their ability to inhibit the enzyme
11.beta.-hydroxysteroid dehydrogenase (HSD) 1, the compounds of
general formula I according to the invention and the corresponding
pharmaceutically acceptable salts thereof are theoretically
suitable for the treatment and/or preventative treatment of all
those conditions or diseases which may be affected by the
inhibition of the 11.beta.-hydroxysteroid dehydrogenase (HSD) 1
activity. Therefore, compounds according to the invention are
particularly suitable for the prevention or treatment of diseases,
particularly metabolic disorders, or conditions such as type 1
diabetes mellitus, type 2 diabetes mellitus, complications of
diabetes (such as e.g. retinopathy, nephropathy or neuropathies,
diabetic foot, ulcers, macroangiopathies, slow or poor wound
healing), metabolic acidosis or ketosis, reactive hypoglycaemia,
hyperinsulinaemia, glucose metabolic disorder, insulin resistance,
metabolic syndrome, dyslipidaemias of different origins,
atherosclerosis and related diseases, obesity, high blood pressure,
chronic heart failure, edema and hyperuricaemia. These substances
are also suitable for preventing beta-cell degeneration such as
e.g. apoptosis or necrosis of pancreatic beta cells. The substances
are also suitable for improving or restoring the functionality of
pancreatic cells, and also of increasing the number and size of
pancreatic beta cells. The compounds according to the invention may
also be used as diuretics or antihypertensives and are suitable for
the prevention and treatment of acute renal failure.
[0189] Additionally, inhibition of 11.beta.-hydroxysteroid
dehydrogenase (HSD) 1 has been shown to lower intraocular pressure
in subjects with ocular hypertension, therefore the compounds could
be used to treat glaucoma.
[0190] In view of the role of 11.beta.-hydroxysteroid dehydrogenase
(HSD) 1 in modulating cortisol levels for interaction with the
glucocorticoid receptor, and the known role of excess
glucocorticoids in bone loss, the compounds may have beneficial
effects in treatment or prevention of osteoporosis.
[0191] Stress and/or glucocorticoids have been shown to influence
cognitive function, and excess cortisol has been associated with
brain neuronal loss or dysfunction. Treatment with an
11.beta.-hydroxysteroid dehydrogenase (HSD) 1 inhibitor may result
in amelioration or prevention of cognitive impairment. Such
compounds may also be useful in treating anxiety or depression.
[0192] The dynamic interaction between the immune system and the
HPA (hypothalamopituitary-adrenal) axis is known, and
glucocorticoids help balance between cell-mediated responses and
humoral responses. The immune reaction is typically biased towards
a humoral response in certain disease states, such as tuberculosis,
leprosy, and psoriasis. More appropriate would be a cell-based
response. An 11.beta.-hydroxysteroid dehydrogenase (HSD) 1
inhibitor would bolster a temporal immune response in association
with immunization to ensure that a cell based response would be
obtained, and as such could be useful in immunomodulation.
[0193] In particular, the compounds according to the invention,
including the physiologically acceptable salts thereof, are
suitable for the prevention or treatment of diabetes, particularly
type 1 diabetes mellitus, type 2 diabetes mellitus, and diabetic
complications.
[0194] The dosage required to achieve the corresponding activity
for treatment or prevention usually depends on the compound which
is to be administered, the patient, the nature and gravity of the
illness or condition and the method and frequency of administration
and is for the patient's doctor to decide. Expediently, the dosage
may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous
route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in
each case administered 1 to 4 times a day. For this purpose, the
compounds of formula I prepared according to the invention may be
formulated, optionally together with other active substances,
together with one or more inert conventional carriers and/or
diluents, e.g. with corn starch, lactose, glucose, microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethylene glycol, propylene glycol,
cetylstearyl alcohol, carboxymethylcellulose or fatty substances
such as hard fat or suitable mixtures thereof, to produce
conventional galenic preparations such as plain or coated tablets,
capsules, powders, suspensions or suppositories.
[0195] The compounds according to the invention may also be used in
conjunction with other active substances, particularly for the
treatment and/or prevention of the diseases and conditions
mentioned above. Other active substances which are suitable for
such combinations include for example those which potentiate the
therapeutic effect of an 11.beta.-hydroxysteroid dehydrogenase
(HSD) 1 inhibitor according to the invention with respect to one of
the indications mentioned and/or which allow the dosage of an
11.beta.-hydroxysteroid dehydrogenase (HSD) 1 inhibitor according
to the invention to be reduced. Therapeutic agents which are
suitable for such a combination include, for example, antidiabetic
agents such as metformin, sulfonylureas (e.g. glibenclamide,
tolbutamide, glimepiride), nateglinide, repaglinide,
thiazolidinediones (e.g. rosiglitazone, pioglitazone), SGLT 2
inhibitors (e.g. dapagliflozin, remogliflozin etabonate),
PPAR-gamma-agonists (e.g. GI 262570) and antagonists,
PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase
inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (e.g.
Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin),
alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1
analogues (e.g. exendin-4) or amylin. The list also includes
inhibitors of protein tyrosinephosphatase 1, substances that affect
deregulated glucose production in the liver, such as e.g.
inhibitors of glucose-6-phosphatase, or
fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon
receptor antagonists and inhibitors of phosphoenol pyruvate
carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase
and glucokinase activators, lipid lowering agents such as for
example HMG-CoA-reductase inhibitors (e.g. simvastatin,
atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic
acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta
agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol
absorption inhibitors such as, for example, ezetimibe, bile
acid-binding substances such as, for example, cholestyramine,
inhibitors of ileac bile acid transport, HDL-raising compounds such
as CETP inhibitors or ABC1 regulators or active substances for
treating obesity, such as sibutramine or tetrahydrolipostatin,
SDRIs, axokine, leptin, leptin mimetics, antagonists of the
cannabinoid) receptor, MCH-1 receptor antagonists, MC4 receptor
agonists, NPY5 or NPY2 antagonists or .beta.3-agonists such as
SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
[0196] Moreover, combinations with drugs for influencing high blood
pressure, chronic heart failure or atherosclerosis such as e.g.
A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics,
.beta.-blockers, Ca-antagonists, centrally acting
antihypertensives, antagonists of the alpha-2-adrenergic receptor,
inhibitors of neutral endopeptidase, thrombocyte aggregation
inhibitors and others or combinations thereof are suitable.
Examples of angiotensin II receptor antagonists are candesartan
cilexetil, potassium losartan, eprosartan mesylate, valsartan,
telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan,
medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423,
BR-9701, etc. Angiotensin II receptor antagonists are preferably
used for the treatment or prevention of high blood pressure and
complications of diabetes, often combined with a diuretic such as
hydrochlorothiazide.
[0197] A combination with uric acid synthesis inhibitors or
uricosurics is suitable for the treatment or prevention of
gout.
[0198] A combination with GABA-receptor antagonists, Na-channel
blockers, topiramat, protein-kinase C inhibitors, advanced
glycation end product inhibitors or aldose reductase inhibitors may
be used for the treatment or prevention of complications of
diabetes.
[0199] The dosage for the combination partners mentioned above is
usefully 1/5 of the lowest dose normally recommended up to 1/1 of
the normally recommended dose.
[0200] Therefore, in another aspect, this invention relates to the
use of a compound according to the invention or a physiologically
acceptable salt of such a compound combined with at least one of
the active substances described above as a combination partner, for
preparing a pharmaceutical composition which is suitable for the
treatment or prevention of diseases or conditions which can be
affected by inhibiting the enzyme 11.beta.-hydroxysteroid
dehydrogenase (HSD) 1. These are preferably metabolic diseases,
particularly one of the diseases or conditions listed above, most
particularly diabetes or diabetic complications.
[0201] The use of the compound according to the invention, or a
physiologically acceptable salt thereof, in combination with
another active substance may take place simultaneously or at
staggered times, but particularly within a short space of time. If
they are administered simultaneously, the two active substances are
given to the patient together; while if they are used at staggered
times the two active substances are given to the patient within a
period of less than or equal to 12 hours, but particularly less
than or equal to 6 hours.
[0202] Consequently, in another aspect, this invention relates to a
pharmaceutical composition which comprises a compound according to
the invention or a physiologically acceptable salt of such a
compound and at least one of the active substances described above
as combination partners, optionally together with one or more inert
carriers and/or diluents.
[0203] Thus, for example, a pharmaceutical composition according to
the invention comprises a combination of a compound of formula I
according to the invention or a physiologically acceptable salt of
such a compound and at least one angiotensin II receptor antagonist
optionally together with one or more inert carriers and/or
diluents.
[0204] The compound according to the invention, or a
physiologically acceptable salt thereof, and the additional active
substance to be combined therewith may both be present together in
one formulation, for example a tablet or capsule, or separately in
two identical or different formulations, for example as a so-called
kit-of-parts.
[0205] The Examples that follow are intended to illustrate the
present invention without restricting it. The terms "ambient
temperature" and "room temperature" are used interchangeably and
designate a temperature of about 20.degree. C.
Preparation of the Starting Compounds
Example I
##STR00043##
[0206] 4-Methyl-2-phenylethynyl-pyridine
[0207] Phenylacetylene (15.4 mL) is added to a mixture of
2-bromo-4-methyl-pyridine (20.0 g), CuI (2.2 g), and
Pd(PPh.sub.3).sub.2Cl.sub.2 (4.1 g) in triethylamine (600 mL) kept
under argon atmosphere. The mixture is stirred at ambient
temperature overnight. Then, water is added and the resulting
mixture is extracted with diethyl ether. The combined organic
extracts are washed with brine and dried (MgSO.sub.4). The solvent
is removed under reduced pressure and the residue is purified by
chromatography on silica gel (cyclohexane/ethyl acetate
9:1->4:1) to give the product as an oil.
[0208] Yield: 18.6 g (83% of theory)
[0209] Mass spectrum (ESI.sup.+): m/z=194 [M+H].sup.+
Example II
##STR00044##
[0210] 4-Methyl-2-phenethyl-pyridine
[0211] A mixture of 4-methyl-2-phenylethynyl-pyridine (18.2 g) and
10% palladium on carbon (2.0 g) in methanol (300 mL) is stirred
under hydrogen atmosphere (50 psi) at ambient temperature until the
triple bond is completely reduced (20 h). The mixture is filtrered
and the solvent is removed under reduced pressure.
[0212] Yield: 17.6 g (95% of theory)
[0213] Mass spectrum (ESI.sup.+): m/z=198 [M+H].sup.+
Example III
##STR00045##
[0214] 1,4-Dimethyl-2-phenethyl-pyridinium iodide
[0215] Iodomethane (8.3 mL) is added to a solution of
4-methyl-2-phenethyl-pyridine (17.5 g) in acetonitrile (70 mL). The
resulting solution is stirred at room temperature overnight before
another portion of iodomethane (2.8 mL) is added and the solution
is further stirred at ca. 35.degree. C. for another 14 h. After
cooling to room temperature, the precipitate is separated by
filtration, washed with acetonitrile, and dried at 50.degree.
C.
[0216] Yield: 20.9 g (69% of theory)
[0217] Mass spectrum (ESI.sup.+): m/z=212
[1,4-dimethyl-2-phenethyl-pyridinium].sup.+
Example IV
##STR00046##
[0218] 1,4-Dimethyl-6-phenethyl-1,2,3,6-tetrahydro-pyridine and
1,4-dimethyl-2-phenethyl-1,2,3,6-tetrahydro-pyridine
[0219] Sodium borohydride (2.9 g) is added in one portion to a
mixture of 1,4-dimethyl-2-phenethyl-pyridinium iodide (20.9 g) and
sodium hydroxide (23.9 g) in water (60 mL) and methanol (75 mL).
The mixture is stirred at 60.degree. C. for 1 h and then cooled to
room temperature. The reaction mixture is extracted with diethyl
ether and the organic extracts are dried (MgSO.sub.4). After
removing the solvent, the residue is purified by chromatography on
silica gel (dichloromethane/methanol 30:1->9:1) to give a
mixture of the two title compounds (ca. 3:1).
[0220] Yield: 16.4 g (61% of theory)
[0221] Mass spectrum (ESI.sup.+): m/z=216 [M+H].sup.+
Example V
##STR00047##
[0222]
1,11-Dimethyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene
[0223] A mixture of
1,4-dimethyl-6-phenethyl-1,2,3,6-tetrahydro-pyridine and
1,4-dimethyl-2-phenethyl-1,2,3,6-tetrahydro-pyridine (ca. 3:1, 1.0
g) dissolved in polyphosphoric acid (5 mL) is stirred at
150.degree. C. for 2 d. After cooling to ca. 80.degree. C., water
(30 mL) is added and the mixture is stirred vigorously for another
5 min. Then, the mixture is cooled in an ice bath, more water is
added, and the mixture is basified using 40% NaOH in water. The
resulting mixture is extracted with ethyl acetate, the combined
organic extracts are washed with brine and dried (MgSO.sub.4). The
solvent is removed under reduced pressure to yield the title
compound.
[0224] Yield: 0.76 g (76% of theory)
[0225] Mass spectrum (ESI.sup.+): m/z=216 [M+H].sup.+
Example VI
##STR00048##
[0226]
1-Methyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene
[0227] 1-Chloroethyl chloroformate (3.8 mL) is added dropwise to a
mixture of
1,11-dimethyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene
(0.75 g) and NaHCO.sub.3 (2.9 g) in 1,2-dichloroethane (3.5 mL)
chilled in an ice bath. The reaction mixture is warmed to room
temperature in the cooling bath and stirred overnight. Then,
dichloromethane (20 mL) is added and the precipitate is removed by
filtration. The filtrate is concentrated under reduced pressure and
the residue is dissolved in methanol (20 mL). The resulting
solution is stirred at reflux for 2 h. The solution is concentrated
and the residue is purified by HPLC (water/MeCN/NH.sub.3) to give
the title compound.
[0228] Yield: 0.11 g (16% of theory)
[0229] The following compounds are obtained analogously to Example
VI:
(1)
11,11-Dimethyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocin-6-ol
##STR00049##
[0231] The starting material,
3,11,11-trimethyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocin-6-ol,
may be obtained in analogy to EP 28717 (1981) from
2-benzyl-1,3,3-trimethyl-piperidinone.
(2)
8-Hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxyl-
ic acid methyl ester
##STR00050##
[0233] The starting material,
8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-ca-
rboxylic acid methyl ester, may be obtained in analogy to J. Med.
Chem. 1962, 5, 357-361 and U.S. Pat. No. 3,687,957 (1972) from
8-methoxy-3-methyl-1-oxo-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocin-
e-6-carbonitrile. The methoxy group on the aromatic ring may be
cleaved by using boron tribromide in dichloromethane or hydrobromic
acid in acetic acid (see e.g. J. Med. Chem. 1992, 35, 4135-4142; J.
Med. Chem. 2004, 47, 165-174).
[0234] Alternatively, the starting material may be obtained as
described in Example XXII(1).
Example VII
##STR00051##
[0235] (6-Methoxy-3-oxo-indan-1-yl)-acetic acid methyl ester
[0236] Concentrated sulfuric acid (3.0 mL) is added to
5-methoxy-1-indanone-3-acetic acid (13.0 g) dissolved in methanol
(100 mL). The solution is stirred at reflux temperature for 4 h and
then cooled to room temperature. About two third of the methanol is
removed under reduced pressure and water (100 mL) and ethyl acetate
(200 mL) are added to the remainder. The organic phase is separated
and washed with water, 1 M NaOH solution, and brine. The organic
phase is dried (MgSO.sub.4) and the solvent is evaporated to give
the product as a yellow oil.
[0237] Yield: 13.2 g (95% of theory)
[0238] Mass spectrum (ESI.sup.+): m/z=235 [M+H].sup.+
Example VIII
##STR00052##
[0239] (3-Hydroxyimino-6-methoxy-indan-1-yl)-acetic acid methyl
ester
[0240] (6-Methoxy-3-oxo-indan-1-yl)-acetic acid methyl ester (12.0
g), hydroxylamine hydrochloride (4.6 g), and sodium acetate (5.5 g)
dissolved in water (40 mL) and methanol (50 mL) are stirred at
reflux temperature for 3 h. After cooling to room temperature,
water (100 mL) is added and the solution is extracted with ethyl
acetate. The combined organic extracts are washed with water and
brine and dried (MgSO.sub.4). The solvent is evaporated to give the
product as a brown oil.
[0241] Yield: 12.5 g (98% of theory)
[0242] Mass spectrum (ESI.sup.+): m/z=250 [M+H].sup.+
Example IX
##STR00053##
[0243] 5-Methoxy-3-methoxycarbonylmethyl-indan-1-yl-ammonium
chloride
[0244] A mixture of 10% palladium on carbon (3.0 g),
(3-hydroxyimino-6-methoxy-indan-1-yl)-acetic acid methyl ester
(12.5 g), and concentrated hydrochloric acid (4.7 mL) in methanol
(150 mL) is stirred under hydrogen atmosphere at room temperature
overnight. The mixture is filtered and the filtrate is concentrated
under reduced pressure. The residue is azeotropically dried using
toluene and washed with diisopropyl ether to give the product as a
white solid after drying at 50.degree. C.
[0245] Yield: 13.0 g (100% of theory)
[0246] Mass spectrum (ESI.sup.+): m/z=236 [M+H].sup.+ ([M+H].sup.+
of (3-amino-6-methoxy-indan-1-yl)-acetic acid methyl ester)
Example X
##STR00054##
[0247] 3-Carboxymethyl-5-methoxy-indan-1-yl-ammonium chloride
[0248] 5-Methoxy-3-methoxycarbonylmethyl-indan-1-yl-ammonium
chloride (12.5 g) dissolved in 2 M hydrochloric acid (120 mL) is
stirred at reflux temperature for 3 h. Then, the solvent is removed
and the residue is azeotropically dried using toluene and further
purified by washing with diisopropyl ether. The product is dried at
50.degree. C.
[0249] Yield: 11.8 g (100% of theory)
[0250] Mass spectrum (ESI.sup.+): m/z=222 [M+H].sup.+ ([M+H].sup.+
of (3-amino-6-methoxy-indan-1-yl)-acetic acid)
Example XI
##STR00055##
[0251]
4-Methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-10-one
[0252] 3-Carboxymethyl-5-methoxy-indan-1-yl-ammonium chloride (13.2
g) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide
methyl-p-toluenesulfonate (21.7 g) dissolved in pyridine (500 mL)
are stirred at room temperature for 7 d. Then, the pyridine is
removed under reduced pressure and the residue is taken up in water
(200 mL) and dichloromethane (200 mL). The organic phase is
separated and the aqueous phase is extracted twice with
dichloromethane. The combined organic phases are washed with 1 M
hydrochloric acid, 1 M NaOH solution, and water. After drying
(MgSO.sub.4), the solvent is evaporated under reduced pressure to
yield the product as a beige solid.
[0253] Yield: 3.0 g (29% of theory)
[0254] Mass spectrum (ESI.sup.+): m/z=204 [M+H].sup.+
Example XII
##STR00056##
[0255]
4-Methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene
[0256] 1 M Borane tetrahydrofuran complex (70 mL) is added dropwise
to a solution of
4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-10-one
(3.0 g) in tetrahydrofuran (20 mL) chilled in an ice bath. The
resulting solution is stirred at reflux temperature for 5 h and
then at room temperature overnight. The solution is cooled to ca.
-10.degree. C. and half-concentrated hydrochloric acid (50 mL) is
added carefully. The mixture is stirred at room temperature for 1 h
and an additional hour at reflux temperature. The solvent is
removed and 2 M aqueous NaOH solution (50 mL) is added to the
residue. The resulting mixture is extracted with dichloromethane
and the combined organic extracts are dried (MgSO.sub.4). After
removal of the solvent, the residue is taken up in ethanol (20 mL)
and the resulting solution is treated with oxalic acid (3 mL) to
obtain the oxalate salt of the title compound.
[0257] Yield: 0.8 g (19% of theory)
[0258] Mass spectrum (ESI.sup.+): m/z=190 [M+H].sup.+
Example XIII
##STR00057##
[0259] 4-Hydroxy-9-azonia-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene
bromide
[0260] A solution of
4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (0.50 g
of oxalate salt) in hydrobromic acid (48% in water, 10 mL) is
stirred at reflux temperature for 3 h. Then, the solution is
concentrated under reduced pressure and the residue is
azetropically dried using toluene and ethanol. The residue is
washed with acetone and dried to give the product as a solid.
[0261] Yield: 0.23 g (49% of theory)
[0262] Mass spectrum (ESI.sup.+): m/z=176 [M+H].sup.+ (of free
amine)
[0263] The following compound is obtained analogously to Example
XIII:
(1)
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocin-9-ol
##STR00058##
[0265] Mass spectrum (ESI.sup.+): m/z=232 [M+H].sup.+
[0266] The compound is prepared from
(2R,6S)-9-methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-ben-
zo[d]azocine [tartaric acid salt, for preparation see WO 9959976
(1999)] and isolated as the hydrogen bromide salt.
Example XIV
##STR00059##
[0267]
9-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo-
[d]azocine-3-carboxylic acid tert-butyl ester
[0268] Di-tert-butyl dicarbonate (8.7 g) is added to a solution of
6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol
(12.0 g) and triethylamine (8 ml) in 1,4-dioxane (100 mL) and water
(100 mL). The solution is stirred at room temperature overnight.
Then, ethyl acetate is added and the organic phase is separated.
The aqueous phase is extracted with ethyl acetate and the organic
extract and phase are combined. The organic phase is washed with 1
M hydrochloric acid, water, and brine, and then dried (MgSO.sub.4).
After removal of the solvent under reduced pressure, the residue is
crystallized from diisopropyl ether to give the title compound.
[0269] Yield: 6.5 g (51% of theory)
[0270] Mass spectrum (ESI.sup.+): m/z=332 [M+H].sup.+
[0271] The following compounds are be obtained analogously to
Example XIV:
(1)
(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00060##
[0273] Mass spectrum (ESI.sup.+): m/z=332 [M+NH.sub.4].sup.+
(2)
(2R,6R,11S)-8-Hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano--
benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00061##
[0274] (3)
(2S,6R)-8-Hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2-
,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00062##
[0276] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase
(4)
(2R,6S)-8-Hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00063##
[0278] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase
(5)
(2S,6R)-9-Hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00064##
[0280] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase
(6)
(2R,6S)-9-Hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00065##
[0282] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase
(7)
8-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]-
azocine-3-carboxylic acid tert-butyl ester
##STR00066##
[0283] 8)
(2R,6S)-9-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-me-
thano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00067##
[0285] Mass spectrum (ESI.sup.+): m/z=332 [M+NH.sub.4].sup.+
[0286] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure starting material that in turn may be obtained as described in
Example XIII(1) or by resolution of the racemic mixture by HPLC on
chiral phase. The synthesis of the racemic starting material is
described in EP 521422 (1993).
Example XV
##STR00068##
[0287] (2R,6S)-Trifluoro-methanesulfonic acid
3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoc-
in-10-yl ester
[0288] Trifluoromethanesulfonic anhydride (9.7 mL) is added to a
solution of
3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]a-
zocin-10-ol (13.7 g, the compound may be obtained by reductive
amination of benzaldehyde with
(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
n-10-ol and NaHB(OAc).sub.3 in 1,2-dichloroethane), triethylamine
(43 mL), and 4-dimethylaminopyridine (50 mg) in dichloromethane
(135 mL) chilled to -10.degree. C. under argon atmosphere. The
solution is stirred at ca. -5.degree. C. for 30 min and then at
room temperature overnight. The solution is added to ice-cold water
and then aqueous ammonia solution is added. The resulting mixture
is extracted with dichloromethane, the combined organic extracts
are washed with water and dried (MgSO.sub.4). The solvent is
removed under reduced pressure to give the crude product that is
used without further purification.
[0289] Yield: 18.0 g (93% of theory)
[0290] Mass spectrum (ESI.sup.+): m/z=454 [M+H].sup.+
[0291] The following compounds are obtained analogously to Example
XV:
(1)
6,11,11-Trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H--
2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00069##
[0293] Mass spectrum (ESI.sup.+): m/z=464 [M+H].sup.+
(2)
(2R,6S)-6,11,11-Trimethyl-10-trifluoromethanesulfonyloxy-1,2,5,6-tetra-
hydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl
ester
##STR00070##
[0295] Mass spectrum (ESI.sup.+): m/z=481 [M+NH.sub.4].sup.+
(3)
(2R,6R)-6,11-Dimethyl-8-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-
-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl
ester
##STR00071##
[0297] Mass spectrum (ESI.sup.+): m/z=450 [M+NH.sub.4].sup.+
(4)
6,11,11-Trimethyl-8-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H--
2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00072##
[0298] (5)
(2R,6S)-6,11,11-Trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-
-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid
tert-butyl ester
##STR00073##
[0300] Mass spectrum (ESI.sup.+): m/z=464 [M+NH.sub.4].sup.+
(6) (2R,6R,11R)-Trifluoro-methanesulfonic acid
3-((S)-2,3-dihydro-benzo[1,4]dioxine-2-carbonyl)-6,11-dimethyl-1,2,3,4,5,-
6-hexahydro-2,6-methano-benzo[d]azocin-8-yl ester
##STR00074##
[0302] Mass spectrum (ESI.sup.+): m/z=512 [M+H].sup.+
[0303] The synthesis of the starting material is described in
Example 1 (Table 3).
(7) (2R,6R,11R)-Trifluoro-methanesulfonic acid
3-((R)-2,3-dihydro-benzo[1,4]dioxine-2-carbonyl)-6,11-dimethyl-1,2,3,4,5,-
6-hexahydro-2,6-methano-benzo[d]azocin-8-yl ester
##STR00075##
[0305] Mass spectrum (ESI.sup.+): m/z=512 [M+H].sup.+
[0306] The synthesis of the starting material is described in
Example 2 (Table 3).
(8) (2R,6R,11S)-Trifluoro-methanesulfonic acid
9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,-
6-methano-benzo[d]azocin-8-yl ester
##STR00076##
[0308] Mass spectrum (ESI.sup.+): m/z=488 [M+NH.sub.4].sup.+
(9) (2R,6R,11R)-Trifluoro-methanesulfonic acid
9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,-
6-methano-benzo[d]azocin-8-yl ester
##STR00077##
[0310] Mass spectrum (ESI.sup.+): m/z=488 [M+NH.sub.4].sup.+
Example XVI
##STR00078##
[0311]
(2R,6S)-3-Benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methan-
o-benzo[d]azocine-10-carbonitrile
[0312] Tetrakis(triphenylphosphine)palladium(0) (2.79 g) is added
to a mixture of (2R,6S)-trifluoro-methanesulfonic acid
3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoc-
in-10-yl ester (7.30 g) and zinc cyanide (2.85 g) in
N,N-dimethylformamide (35 mL) kept in argon atmosphere. The
resulting mixture is stirred at 100.degree. C. for 6 h. After
cooling to room temperature, water (300 mL), concentrated ammonia
solution (10 mL), and ethyl acetate (150 mL) are added and the
forming precipitate is separated by filtration. The organic layer
of the filtrate is separated and the aqueous layer is extracted
twice with ethyl acetate. The combined organic phases are washed
with brine and dried (MgSO.sub.4). The solvent is removed under
reduced pressure and the residue is purified by chromatography on
silica gel (cyclohexane/ethyl acetate 19:1) to give the
product.
[0313] Yield: 4.43 g (62% of theory)
[0314] Mass spectrum (ESI.sup.+): m/z=331 [M+H].sup.+
[0315] The following compounds are obtained analogously to Example
XVI:
(1)
(2R,6R,11S)-8-Cyano-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-be-
nzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00079##
[0317] Mass spectrum (ESI.sup.+): m/z=327 [M+NH.sub.4].sup.+
(2)
9-Cyano-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]az-
ocine-3-carboxylic acid tert-butyl ester
##STR00080##
[0319] Mass spectrum (ESI.sup.+): m/z=341 [M+H].sup.+
(3)
(2R,6S)-9-Cyano-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-be-
nzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00081##
[0321] Mass spectrum (ESI.sup.+): m/z=341 [M+H].sup.+
Example XVII
##STR00082##
[0322]
(2R,6S)-3-Benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methan-
o-benzo[d]azocine-10-carboxylic acid ethyl ester
[0323] A solution of
(2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benz-
o[d]azocine-10-carbonitrile (1.14 g) in 80% sulfuric acid (4 mL) is
stirred at 150.degree. C. for 1 h. After cooling to room
temperature, ethanol (30 mL) is added and the solution is stirred
at 100.degree. C. for 2 d. Then, the cooled solution is added to
water (100 mL) and the mixture is basified using 40% aqueous NaOH
solution. The resulting mixture is extracted twice with ethyl
acetate and dried (MgSO.sub.4). The solvent is removed under
reduced pressure to give the crude product.
[0324] Yield: 1.14 g (87% of theory)
[0325] Mass spectrum (ESI.sup.+): m/z=378 [M+H].sup.+
[0326] The following compounds are obtained analogously to Example
XVII:
(1)
6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9--
carboxylic acid ethyl ester
##STR00083##
[0328] Mass spectrum (ESI.sup.+): m/z=288 [M+H].sup.+
[0329] The compound is prepared from
6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-car-
bonitrile applying the procedure described above.
(2)
(2R,6R,11S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-
-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylic acid ethyl
ester
##STR00084##
[0331] Mass spectrum (ESI.sup.+): m/z=274 [M+H].sup.+
[0332] The compound is prepared from
(2R,6R,11S)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
ne-8-carbonitrile applying the procedure described above.
Example XVIII
##STR00085##
[0333]
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d-
]azocine-10-carboxylic acid ethyl ester
[0334] Pd(OH).sub.2 (0.20 g) is added to a solution of
(2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benz-
o[d]azocine-10-carboxylic acid ethyl ester (1.13 g) in ethanol (20
mL). The resulting mixture is stirred under hydrogen atmosphere (50
psi) at room temperature overnight. Then, the catalyst is separated
by filtration and the filtrate is concentrated under reduced
pressure to give the product.
[0335] Yield: 0.61 g (71% of theory)
[0336] Mass spectrum (ESI.sup.+): m/z=288 [M+H].sup.+
[0337] The following compound is obtained analogously to Example
XVIII:
(1)
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocine-10-carbonitrile
##STR00086##
[0338] Example XIX
##STR00087##
[0339]
6,11,11-Trimethyl-9-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[-
d]azocine-3-carboxylic acid tert-butyl ester
[0340] Aqueous 2 M Na.sub.2CO.sub.3 solution (5 mL) is added to a
mixture of
6,11,11-trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H--
2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
(1.00 g) and phenylboronic acid (0.34 g) in N,N-dimethylformamide
(5 mL) in argon atmosphere. The resulting mixture is flushed with
argon and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)
dichloride dichloromethane complex (0.18 g) is added. The mixture
is heated to 100.degree. C. and stirred at this temperature for 4
h. After cooling to room temperature, water is added and the
resulting mixture is extracted with ethyl acetate. The combined
organic extracts are dried (MgSO.sub.4) and the solvent is removed
under reduced pressure. The residue is purified by chromatography
on silica gel (cyclohexane/ethyl acetate 9:1->1:1) to give the
product as a colorless oil.
[0341] Yield: 0.35 g (41% of theory)
[0342] Mass spectrum (ESI.sup.+): m/z=392 [M+H].sup.+
Example XX
##STR00088##
[0343]
6,11,11-Trimethyl-9-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[-
d]azocine
[0344] Trifluoroacetic acid (0.5 mL) is added to a solution of
6,11,11-trimethyl-9-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azoc-
ine-3-carboxylic acid tert-butyl ester (0.30 g) in dichloromethane
(2.5 mL). The solution is stirred at ambient temperature for 1 h
and then concentrated under reduced pressure. The crude
trifluoroacetic acid salt of the title compound is used without
further purification.
[0345] Yield: 0.31 g (100% of theory)
[0346] The following compounds are obtained analogously to Example
XX:
[0347] (Alternatively, in cases in which the purity of the product
is insufficient after applying the procedure described above, the
compounds are purified by HPLC on reversed phase (MeCN/water) to
obtain the pure compounds.)
(1)
(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocine-8-carbonitrile
##STR00089##
[0349] Mass spectrum (ESI.sup.+): m/z=227 [M+NH.sub.4].sup.+
[0350] The compound is obtained as its trifluoroacetic acid
salt.
(2)
6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9--
carbonitrile
##STR00090##
[0352] Mass spectrum (ESI.sup.+): m/z=241 [M+H].sup.+
[0353] The compound is obtained as its trifluoroacetic acid
salt.
(3)
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocin-10-ylamine
##STR00091##
[0355] Mass spectrum (ESI.sup.+): m/z=231 [M+NH.sub.4].sup.+
[0356] The compound is obtained as its double trifluoroacetic acid
salt.
(4)
6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-y-
lamine
##STR00092##
[0358] Mass spectrum (ESI.sup.+): m/z=231 [M+NH.sub.4].sup.+
[0359] The compound is obtained as its double trifluoroacetic acid
salt.
(5)
(2S,6R)-8-Methoxy-6,9,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-meth-
ano-benzo[d]azocine
##STR00093##
[0361] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2S,6R)-8-methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(6)
(2R,6S)-8-Methoxy-6,9,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-meth-
ano-benzo[d]azocine
##STR00094##
[0363] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2R,6S)-8-methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(7)
(2S,6R)-9-Methoxy-6,8,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-meth-
ano-benzo[d]azocine
##STR00095##
[0365] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2S,6R)-9-methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(8)
(2R,6S)-9-Methoxy-6,8,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-meth-
ano-benzo[d]azocine
##STR00096##
[0367] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2R,6S)-9-methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(9)
8,9-Dimethoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benz-
o[d]azocine
##STR00097##
[0368] (10)
8-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azo-
cin-9-ol
##STR00098##
[0369] (11)
9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azo-
cin-8-ol
##STR00099##
[0370] (12)
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
ne-9-carbonitrile
##STR00100##
[0372] Mass spectrum (ESI.sup.+): m/z=241 [M+H].sup.+
[0373] The compound is obtained as its trifluoroacetic acid
salt.
(13)
(cis-4-Amino-cyclohexyl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,-
6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
##STR00101##
[0375] The starting material,
{cis-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-me-
thano-benzo[d]azocine-3-carbonyl]-cyclohexyl}-carbamic acid
tert-butyl ester, is obtained from
(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
n-10-ol and cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic
acid employing procedure B.
(14)
[(1R,3R)-3-Amino-cyclopentyl]-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetr-
ahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
##STR00102##
[0377] Isolated as the trifluoroacetic acid salt.
[0378] The starting material,
{(1R,3R)-3-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocine-3-carbonyl]-cyclopentyl}-carbamic acid tert-butyl
ester, is obtained from
(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
ne and (1R,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic
acid employing procedure B.
Example XXI
##STR00103##
[0379]
[(2R,6S)-3-Benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-metha-
no-benzo[d]azocin-10-yl]-methanol
[0380] A solution of
(2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benz-
o[d]azocine-10-carboxylic acid ethyl ester (0.96 g) in
tetrahydrofuran (2 mL) is added dropwise to LiAlH.sub.4 (1.6 mL,
2.4 mol/L in tetrahydrofuran) in tetrahydrofuran (1.5 mL). The
reaction mixture is stirred at ambient temperature for 90 min.
Then, water (4 mL) is added carefully and the resulting mixture is
extracted with ethyl acetate. The combined organic extracts are
washed with water and brine and dried (MgSO.sub.4). The solvent is
removed under reduced pressure to give the product.
[0381] Yield: 0.62 g (72% of theory)
[0382] Mass spectrum (ESI.sup.+): m/z=336 [M+H].sup.+
Example XXII
##STR00104##
[0383]
(2R,6S)-6,10,11,11-Tetramethyl-1,2,3,4,5,6-hexahydro-2,6-methano-be-
nzo[d]azocine
[0384] 10% Palladium on carbon (0.10 g) is added to a solution of
(2R,6S)-(3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-ben-
zo[d]azocin-10-yl)-methanol (0.60 g) in methanol (10 mL). The
mixture is stirred under hydrogen atmosphere (50 psi) at room
temperature overnight. Then, another portion of 10% palladium on
carbon (0.2 g) and 4 M hydrochloric acid (1 mL) are added and the
mixture is further stirred in hydrogen atmosphere for 4 h. After
the catalyst is separated by filtration, the filtrate is
concentrated under reduced pressure to give the hydrochloric acid
salt of the title product.
[0385] Yield: 0.50 g (100% of theory)
[0386] The following compound is obtained analogously to Example
XXII:
(1)
8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-
-carboxylic acid methyl ester
##STR00105##
[0388] The compound may be obtained from
1-hydroxy-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]az-
ocine-6-carboxylic acid methyl ester employing the procedure
described above. Alternatively, the reduction may be conducted in
analogy to J. Org. Chem. 1987, 52, 5233-5239.
Example XXIII
##STR00106##
[0389]
(2R,6S)-10-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methan-
o-benzo[d]azocine-3-carboxylic acid tert-butyl ester
[0390] A flask charged with a stir bar,
(2R,6S)-6,11,11-trimethyl-10-trifluoromethanesulfonyloxy-1,2,5,6-tetrahyd-
ro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl
ester (4.0 g), benzhydrylideneamine (3.2 mL), Cs.sub.2CO.sub.3 (5.6
g), and toluene (80 mL) is flushed with argon for 10 min. Then,
2,2'-bis-diphenylphosphanyl-[1,1']binaphthalenyl (0.35 g) and
tris(dibenzylideneacetone)dipalladium (0.18 g) are added and the
resulting mixture is stirred at reflux temperature overnight. After
cooling to room temperature, the reaction mixture is washed with
water and concentrated. The residue is taken up in tetrahydrofuran
and 2 M hydrochloric acid is added. The mixture is stirred at
ambient temperature for 4 h. The precipitate is separated by
filtration and the filtrate is concentrated under reduced pressure.
The residue is purified by chromatography on silica gel
(cyclohexane/ethyl acetate 1:7) to give the product as a brown
oil.
[0391] Yield: 0.83 g (29% of theory)
[0392] Mass spectrum (ESI.sup.+): m/z=331 [M+H].sup.+
[0393] The following compounds are obtained analogously to Example
XXIII:
(1)
9-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]az-
ocine-3-carboxylic acid tert-butyl ester
##STR00107##
[0395] Mass spectrum (ESI.sup.+): m/z=331 [M+NH.sub.4].sup.+
(2)
8-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]az-
ocine-3-carboxylic acid tert-butyl ester
##STR00108##
[0397] Mass spectrum (ESI.sup.+): m/z=331 [M+NH.sub.4].sup.+
Example XXIV
##STR00109##
[0398]
(2R,6S)-10-Fluoro-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-metha-
no-benzo[d]azocine
[0399] A solution of nitrosonium tetrafluoroborate (0.25 g) in
1,4-dioxane (2 mL) is added to a solution of
(2R,6S)-10-amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benz-
o[d]azocine-3-carboxylic acid tert-butyl ester (0.10 g) in dioxane
(2 mL). The solution is heated to 50.degree. C. and stirred at this
temperature overnight. The reaction solution is diluted with
methanol and then concentrated under reduced pressure. The residue
is purified by HPLC on reversed phase
(MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to yield the title product.
[0400] Yield: 25 mg (36% of theory)
[0401] Mass spectrum (ESI.sup.+): m/z=234 [M+H].sup.+
[0402] The following compounds are obtained analogously to Example
XXIV:
(1)
8-Fluoro-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]a-
zocine
##STR00110##
[0403] (2)
9-Fluoro-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-be-
nzo[d]azocine
##STR00111##
[0405] In cases in which the tert-butyloxycarbonyl group is not
completely cleaved off after the reaction the crude product is
treated with trifluoroacetic acid in dichloromethane.
Example XXV
##STR00112##
[0406]
8,9-Dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocine-3-carboxylic acid tert-butyl ester
[0407] Di-tert-butyl dicarbonate (0.34 g) is added to a solution of
6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8,9-d-
iol (0.44 g) and triethylamine (0.43 mL) in dichloromethane (5 mL).
The solution is stirred at room temperature for 2 h. Then, the
solution is washed twice with water and once with brine. After
drying (MgSO.sub.4), the solvent is removed under reduced pressure
to yield the product.
[0408] Yield: 0.43 g (80% of theory)
[0409] Mass spectrum (ESI.sup.-): m/z=346 [M-H].sup.-
Example XXVI
##STR00113##
[0410]
8,9-Methylenedioxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
[0411] A mixture of
8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d-
]azocine-3-carboxylic acid tert-butyl ester (0.21 g),
K.sub.2CO.sub.3 (0.19 g), and diiodomethane (54 .mu.L) in
N,N-dimethylformamide (5 mL) is heated to 100.degree. C. and
stirred at this temperature for 2 h. Then, another portion of
diiodomethane (54 .mu.L) and K.sub.2CO.sub.3 (0.18 g) is added and
the mixture is further stirred at 100.degree. C. for 5 h. After
cooling to room temperature, water is added and the resulting
mixture is extracted with ethyl acetate. The combined organic
extracts are washed with brine and dried (MgSO.sub.4). After
removal of the solvent, the residue is purified by chromatography
on silica gel (cyclohexane/ethyl acetate 1:1).
[0412] Yield: 0.20 g (93% of theory)
[0413] Mass spectrum (ESI.sup.+): m/z=360 [M+H].sup.+
Example XXVII
##STR00114##
[0414]
8,9-Methylenedioxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-meth-
ano-benzo[d]azocine
[0415] Isopropanolic hydrochloric acid (5 mol/L, 0.55 mL) is added
to
8,9-methylenedioxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-be-
nzo[d]azocine-3-carboxylic acid tert-butyl ester (0.19 g) dissolved
in dichloromethane (2 mL). The resulting solution is stirred for 2
h at room temperature. Then, the solution is concentrated under
reduced pressure to give the title product as its hydrochloric acid
salt.
[0416] Yield: 0.15 g (97% of theory)
[0417] Mass spectrum (ESI.sup.+): m/z=260 [M+H].sup.+
Example XXVIII
##STR00115##
[0418] 2-(2-Methoxy-benzyl)-3,3-dimethyl-piperidin-4-ol
[0419] Sodium borohydride (0.31 g) is added to
2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-one (2.00 g, prepared
according to J. Med. Chem. 2002, 45, 3755-3765 from racemic
starting material) dissolved in methanol (20 mL). The solution is
stirred at room temperature for 3 h and then 1 M sodium hydroxide
solution (40 mL) is added. After stirring for another 10 min, the
mixture is extracted with dichloromethane. The combined organic
extracts are washed with water and dried (MgSO.sub.4). The solvent
is evaporated to give the title product.
[0420] Yield: 2.00 g (99% of theory)
[0421] Mass spectrum (ESI.sup.+): m/z=250 [M+H].sup.+
Example XXIX
##STR00116##
[0422]
10-Methoxy-11,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d-
]azocine
[0423] A solution of
2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-ol (0.80 g) in
polyphosphoric acid (10 mL) is stirred at 120.degree. C. overnight.
After cooling the solution to ca. 80.degree. C., water (300 mL) is
added and the mixture is stirred vigorously for another 10 min.
Then, the mixture is cooled in an ice bath, more water is added,
and the mixture is basified using 10 M aqueous NaOH solution. The
resulting mixture is extracted with ethyl acetate, the combined
organic extracts are washed with brine and dried (MgSO.sub.4). The
solvent is removed under reduced pressure to yield the title
product that is used without further purification.
[0424] Yield: 0.36 g (49% of theory)
[0425] The following compound is obtained analogously to Example
XXIX:
(1)
(2S,6R)-9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano--
benzo[d]azocine
##STR00117##
[0427] The racemic product mixture is resolved into its enantiomers
by using HPLC on chiral phase. The compound may also be obtained in
analogy to the procedure described in J. Med. Chem. 1997, 40,
2922-2930.
Example XXX
##STR00118##
[0428]
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d-
]azocine
[0429] 10% Pd/C (0.20 g) is added to a solution of
(2R,6S)-trifluoro-methanesulfonic acid
3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoc-
in-10-yl ester (0.50 g) in ethanol (10 mL). The resulting mixture
is shaken under hydrogen atmosphere (50 psi) at room temperature
overnight. Then, the catalyst is separated by filtration and
Pd(OH).sub.2 (0.2 g) is added to the filtrate (the benzyl group was
not completely removed after the treatment in the presence of
Pd/C). The mixture is shaken in hydrogen atmosphere (50 psi) at
room temperature for another 16 h. The catalyst is separated and
the filtrate is concentrated under reduced pressure to give the
crude product that is used without further purification.
[0430] Yield: 0.23 g (98% of theory)
[0431] The following compound is obtained analogously to Example
XXX:
(1) 2,3,4,5,6,7-Hexahydro-2,6-methano-1H-azocino[5,4-b]indole
(racemic mixture of the diastereomer shown)
##STR00119##
[0433] The debenzylation of the starting compound is carried out
with Pd(OH).sub.2 as described above.
Example XXXI
##STR00120##
[0434]
2,2,2-Trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tet-
rahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
[0435] Trifluoroacetic anhydride (5.0 mL) is added to a solution of
the hydrobromic acid salt of
(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
n-10-ol (5.0 g) and triethylamine (5.5 mL) in dichloromethane (50
mL) chilled in an ice bath. The resulting solution is stirred at
ambient temperature overnight. Then, water is added, the resulting
mixture is stirred for an additional 15 min, and the organic phase
is separated. The organic phase is washed with water and brine,
dried (Na.sub.2SO.sub.4), and the solvent is evaporated. The
residue is purified by chromatography on silica gel (ethyl
acetate/cyclohexane 1:4) to give the product as a foam-like
solid.
[0436] Yield: 3.34 g (64% of theory)
[0437] Mass spectrum (ESI.sup.+): m/z=328 [M+H].sup.+
[0438] The following compounds are obtained analogously to Example
XXXI:
(1)
2,2,2-Trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-
-methano-benzo[d]azocin-3-yl]-ethanone
##STR00121##
[0440] Mass spectrum (ESI.sup.+): m/z=312 [M+H].sup.+
(2)
2,2,2-Trifluoro-1-[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahy-
dro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
##STR00122##
[0442] Mass spectrum (ESI.sup.+): m/z=314 [M+H].sup.+
(3)
2,2,2-Trifluoro-1-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahy-
dro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
##STR00123##
[0444] Mass spectrum (ESI.sup.+): m/z=314 [M+H].sup.+
Example XXXII
##STR00124##
[0445]
2,2,2-Trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-9-nitro-1,2-
,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
[0446] Nitric acid (0.4 mL) is slowly added to a solution of
2,2,2-trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydr-
o-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (2.9 g) in acetic
acid (5 mL) chilled in an ice bath. The ice bath is removed and the
solution is stirred at ambient temperature overnight. The solution
is poured into ice-cold water and the resulting mixture is
extracted with ethyl acetate. The combined extracts are washed with
brine and dried (Na.sub.2SO.sub.4). After removal of the solvent
under reduced pressure, the residue is purified by chromatography
on silica gel (ethyl acetate/cyclohexane 1:9->1:3).
[0447] Yield: 1.3 g (39% of theory)
[0448] Mass spectrum (ESI.sup.-): m/z=371 [M-H].sup.-
[0449] The following compound is obtained analogously to Example
XXXII:
(1)
2,2,2-Trifluoro-1-[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-9-nitro-1,2,5,6-
-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
##STR00125##
[0451] Mass spectrum (ESI.sup.+): m/z=359 [M+H].sup.+
Example XXXIII
##STR00126##
[0452]
2,2,2-Trifluoro-1-[(2R,6S)-10-methoxy-6,11,11-trimethyl-9-nitro-1,2-
,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
[0453] Methyl iodide (80 .mu.L) is added to a mixture of
2,2,2-trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-9-nitro-1,2,5,6-t-
etrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (0.40 g) and
potassium carbonate (0.17 g) in N,N-dimethylformamide (5 mL). The
mixture is stirred at room temperature overnight, before another
portion of methyl iodide (80 .mu.L) and potassium carbonate (0.16
g) are added. The mixture is stirred for another 6 h at room
temperature. Then, water and ethyl acetate are added, the organic
phase is separated, and the aqueous phase is extracted with ethyl
acetate. The combined organic phases are washed with brine and
dried (Na.sub.2SO.sub.4). The solvent is evaporated to give the
crude product that is used without further purification.
[0454] Yield: 0.41 g (100% of theory)
[0455] Mass spectrum (ESI.sup.+): m/z=387 [M+H].sup.+
[0456] The following compounds are obtained analogously to Example
XXXIII:
(1)
(2S,6R)-8-Methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00127##
[0458] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2S,6R)-8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(2)
(2R,6S)-8-Methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00128##
[0460] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2R,6S)-8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(3)
(2S,6R)-9-Methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00129##
[0462] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2S,6R)-9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(4)
(2R,6S)-9-Methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00130##
[0464] The compound may be obtained by resolution of the racemic
mixture by HPLC on chiral phase or by using the enantiomerically
pure
(2R,6S)-9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
(5)
8,9-Dimethoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benz-
o[d]azocine-3-carboxylic acid tert-butyl ester
##STR00131##
[0466] Twice the amount of methyl iodide and potassium carbonate as
described in the procedure above are employed to prepare the
compound from
8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-be-
nzo[d]azocine-3-carboxylic acid tert-butyl ester.
(6)
9-Hydroxy-8-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methan-
o-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00132##
[0468] The compound is obtained in a mixture with
8-hydroxy-9-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocine-3-carboxylic acid tert-butyl ester and
8,9-dimethoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d-
]azocine-3-carboxylic acid tert-butyl ester from
8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d-
]azocine-3-carboxylic acid tert-butyl ester that may be resolved by
HPLC on reversed phase (MeCN/H.sub.2O).
(7)
8-Hydroxy-9-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methan-
o-benzo[d]azocine-3-carboxylic acid tert-butyl ester
##STR00133##
[0470] The compound is obtained in a mixture with
9-hydroxy-8-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocine-3-carboxylic acid tert-butyl ester and
8,9-dimethoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d-
]azocine-3-carboxylic acid tert-butyl ester from
8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d-
]azocine-3-carboxylic acid tert-butyl ester that may be resolved by
HPLC on reversed phase (MeCN/H.sub.2O).
(8)
2,2,2-Trifluoro-1-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-9-nitro-1,2,5,6-
-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
##STR00134##
[0472] Mass spectrum (ESI.sup.+): m/z=373 [M+H].sup.+
(9)
9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]-
azocine
##STR00135##
[0473] (10)
(2S,6R)-9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-ben-
zo[d]azocine
##STR00136##
[0475] The compound may be obtained from the racemic mixture by
HPLC on chiral phase.
Example XXXIV
##STR00137##
[0476]
1-[(2R,6S)-10-Benzylamino-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahy-
dro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone
[0477]
2,2,2-Trifluoro-1-[(2R,6S)-10-methoxy-6,11,11-trimethyl-9-nitro-1,2-
,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (0.41
g) is combined with benzylamine (0.7 mL) and the resulting mixture
is stirred at 70.degree. C. overnight. After cooling to room
temperature, the mixture is purified by HPLC on reversed phase
(MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give the product as an
oil.
[0478] Yield: 0.19 g (38% of theory)
[0479] Mass spectrum (ESI.sup.+): m/z=462 [M+H].sup.+
[0480] The following compound is obtained analogously to Example
XXXIV:
(1)
1-[(2R,6R,11S)-8-Benzylamino-6,11-dimethyl-9-nitro-1,2,5,6-tetrahydro--
4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone
##STR00138##
[0481] Example XXXV
##STR00139##
[0482]
(5R,9S)-4,5,6,7,8,9-hexahydro-9,12,12-trimethyl-5,9-methano-1H-imid-
azo[5,4-i][3]benzazocine
[0483] A mixture of Raney-Ni (0.1 g),
1-[(2R,6S)-10-benzylamino-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-
-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (0.19
g), and formic acid (10 mL) is stirred in hydrogen atmosphere at
50.degree. C. overnight. Then, the catalyst is separated by
filtration and the filtrate is concentrated. The remainder is taken
up in methanol (10 mL) and treated with 4 M aqueous NaOH solution
(2 mL) at 50.degree. C. overnight. After cooling to room
temperature, the solution is neutralized with 2 M hydrochloric acid
and the solvent is removed. The residue is purified by HPLC on
reversed phase (MeCN/H.sub.2O).
[0484] Yield: 35 mg (33% of theory)
[0485] The following compound is obtained analogously to Example
XXXV:
(1)
(6R,10R,12S)-5,6,7,8,9,10-Hexahydro-10,12-dimethyl-6,10-methano-1H-imi-
dazo[5,4-i][3]benzazocine
##STR00140##
[0487] Mass spectrum (ESI.sup.+): m/z=242 [M+H].sup.+
Example XXXVI
##STR00141##
[0488]
(2R,6S)-6,11,11-Trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-he-
xahydro-2,6-methano-benzo[d]azocine-8-sulfonyl chloride and
(2R,6S)-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydr-
o-2,6-methano-benzo[d]azocine-9-sulfonyl chloride
[0489] Chlorosulfonic acid (1.15 mL) is slowly added to a solution
of
2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-me-
thano-benzo[d]azocin-3-yl]-ethanone (0.90 g) in dichloromethane (10
mL) at room temperature. Then, the solution is stirred at ambient
temperature overnight. The solution is poured into ice-cold water
and the resulting mixture is extracted with ethyl acetate. The
combined organic extracts are washed with brine and dried
[0490] (MgSO.sub.4). The solvent is removed under reduced pressure
to give the crude title compounds as a mixture that is used without
further purification.
[0491] Yield: 1.18 g
Example XXXVII
##STR00142##
[0492]
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d-
]azocine-8-sulfonic acid dimethylamide and
(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
ne-9-sulfonic acid dimethylamide
[0493] Dimethylamine (3.3 mL, 2 M in tetrahydrufuran) is added to a
mixture of
(2R,6S)-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydr-
o-2,6-methano-benzo[d]azocine-8-sulfonyl chloride and
(2R,6S)-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydr-
o-2,6-methano-benzo[d]azocine-9-sulfonyl chloride (0.90 g, crude
product from Example XXXVI) dissolved in ethanol (5 mL) and chilled
in an ice bath. The cooling bath is removed and the solution is
stirred at room temperature for 2 h. Then, 4 M aqueous NaOH
solution (2.2 mL) is added to cleave off the trifluoroacetyl group.
After stirring at room temperature for 1 h, the solution is diluted
with water and the resulting mixture is extracted with ethyl
acetate. The combined extracts are washed with brine and dried
(MgSO.sub.4). The solvent is removed and the residue is purified by
HPLC on reversed phase (MeCN/H.sub.2O/NF1.sub.3) to give the two
title compounds separated.
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-
e-8-sulfonic acid dimethylamide: Yield: 500 mg (71% of theory)
[0494] Mass spectrum (ESI.sup.+): m/z=323 [M+H].sup.+
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-
e-9-sulfonic acid dimethylamide: Yield: 50 mg (7% of theory)
[0495] Mass spectrum (ESI.sup.+): m/z=323 [M+H].sup.+
[0496] The following compounds are obtained analogously to Example
XXXVII:
(1)
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocine-8-sulfonic acid methylamide
##STR00143##
[0498] Mass spectrum (ESI.sup.+): m/z=309 [M+H].sup.+
[0499] Methylamine is used as coupling partner.
(2)
(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocine-8-sulfonic acid amide
##STR00144##
[0501] Mass spectrum (ESI.sup.+): m/z=295 [M+H].sup.+
[0502] Ammonia is used as coupling partner.
Example XXXVIII
##STR00145##
[0503]
1-[(2R,6S)-8-Acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-met-
hano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone and
1-[(2R,6S)-9-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone
[0504] Acetyl chloride (0.25 mL) is added to a suspension of
AlCl.sub.3 (1.3 g) in dichloromethane (5 mL) chilled in an ice
bath. After stirring the mixture for 5 min,
(2R,6S)-2,2,2-trifluoro-1-(6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-me-
thano-benzo[d]azocin-3-yl)-ethanone (1.0 g) dissolved in
dichloromethane (5 mL) is added dropwise. The mixture is stirred at
ambient temperature overnight and then poured into ice-cold
half-concentrated hydrochloric acid (20 mL). The resulting mixture
is extracted with dichloromethane and the combined organic extracts
are washed with water, aqueous NaHCO.sub.3 solution, and brine and
dried (MgSO.sub.4). The solvent is removed and the residue is
purified by chromatography on silica gel (cyclohexane/ethyl acetate
3:1->1:1) to give the two regioisomeric title compounds in a ca.
3:1 mixture.
[0505] Yield: 0.83 g (73% of theory)
[0506] Mass spectrum (ESI.sup.+): m/z=354 [M+H].sup.+
Example XXXIX
##STR00146##
[0507]
1-[(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benz-
o[d]azocin-8-yl]-ethanone and
1-[(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocin-9-yl]-ethanone
[0508] 4 M NaOH solution (2.5 mL) is added to a ca. 3:1 mixture of
1-[(2R,6S)-8-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone and
1-[(2R,6S)-9-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (0.83 g) in methanol
(10 mL). The resulting solution is stirred at room temperature
overnight. Then, the solution is neutralized with 1 M hydrochloric
acid and concentrated. The residue is purified by HPLC on reversed
phase (acetonitrile/water/NH.sub.3) to give the two title compounds
separated.
[0509] Yield: 0.35 g of
1-[(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocin-8-yl]-ethanone and 0.07 g of
1-[(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocin-9-yl]-ethanone (combined 71% of theory)
[0510] Mass spectrum (ESI.sup.+): m/z=258 [M+H].sup.+
[0511] The following compounds are obtained analogously to Example
XXXIX:
(1)
(2R,6R,11S)-8-Hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano--
benzo[d]azocine-9-carbonitrile
##STR00147##
[0513] Mass spectrum (ESI.sup.+): m/z=243 [M+H].sup.+
(2)
(2R,6S)-8-Methanesulfonyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6--
methano-benzo[d]azocine
##STR00148##
[0515] Mass spectrum (ESI.sup.+): m/z=294 [M+H].sup.+
(3)
(2R,6S)-10-Methanesulfonyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-
-methano-benzo[d]azocine
##STR00149##
[0517] Mass spectrum (ESI.sup.+): m/z=294 [M+H].sup.+
(4)
(6R,10S)-5,6,7,8,9,10-Hexahydro-2,10,12,12-tetramethyl-6,10-methano-1H-
-imidazo[5,4-i][3]benzazocine
##STR00150##
[0518] (5)
(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-6,10-methano-
-1H-imidazo[5,4-i][3]benzazocine
##STR00151##
[0519] Example XL
##STR00152##
[0520]
(2R,6R,11R)-8-Methoxy-6,11-dimethyl-7,9-dinitro-1,2,3,4,5,6-hexahyd-
ro-2,6-methano-benzo[d]azocine
[0521] Ammonium nitrate (2.2 g) is added to a solution of
(2R,6R,11R)-8-methoxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-ben-
zo[d]azocine (7.0 g) in concentrated sulfuric acid (25 mL) chilled
to -5.degree. C. Then, the cooling bath is removed and the solution
is stirred at ambient temperature for 3 h. The reaction solution is
diluted with water and basified using 1 M aqueous NaOH solution.
The resulting mixture is extracted with dichloromethane, the
combined extracts are dried (MgSO.sub.4) and the solvent is
evaporated. The residue is purified by HPLC on reversed phase
(MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give the product as the
trifluoroacetic acid salt.
[0522] Yield: 1.27 g (11% of theory)
[0523] Mass spectrum (ESI.sup.+): m/z=322 [M+H].sup.+
Example XLI
##STR00153##
[0524]
(2R,6R,11R)-7,9-Dichloro-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-me-
thano-benzo[d]azocin-8-ol
[0525] SO.sub.2Cl.sub.2 (1.6 mL) is added to a solution of
(2R,6R,11R)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
n-8-ol (2.0 g) in acetic acid (100 mL). The solution is stirred at
ambient temperature for 2 h, before another portion of
SO.sub.2Cl.sub.2 (0.4 mL) is added. After stirring for another 1 h,
the solution is concentrated under reduced pressure to give the
crude acetic acid salt of the product that is dissolved in a
solution of hydrogen chloride in ethylacetate (20 mL). The solution
is concentrated and the residue is triturated with ether to give
the hydrogen chloride salt of the title compound.
[0526] Yield: 2.40 g (81% of theory)
[0527] Mass spectrum (ESI.sup.+): m/z=286/288/290 (2Cl)
[m+H].sup.+
[0528] The following compound is obtained analogously to Example
XLI:
(1)
(2R,6S)-7,9-Dichloro-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[-
d]azocin-8-ol
##STR00154##
[0530] Mass spectrum (ESI.sup.+): m/z=272/274/276 (2Cl)
[M+H].sup.+
Example XLII
##STR00155##
[0531]
(2R,6R,11R)-7-Chloro-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methan-
o-benzo[d]azocin-8-ol
[0532] A mixture of 10% Pd/C (0.6 g) and the hydrogen chloride salt
of
(2R,6R,11R)-7,9-dichloro-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano--
benzo[d]azocin-8-ol (1.0 g) in methanol (40 mL) is shaken in
hydrogen atmosphere (3 bar) at room temperature for 24 h. Then, the
catalyst is separated by filtration and the filtrate is
concentrated. The residue is purified by HPLC on reversed phase
(MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give the trifluoroacetic acid
salt of the title compound.
[0533] Yield: 0.59 g (52% of theory)
[0534] Mass spectrum (ESI.sup.+): m/z=252/254 (Cl) [M+H].sup.+
[0535] The following compound is obtained analogously to Example
XLII:
(1)
(2R,6S)-7-Chloro-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocin-8-ol
##STR00156##
[0537] Mass spectrum (ESI.sup.+): m/z=238/240 (Cl) [M+H].sup.+
Example XLIII
##STR00157##
[0538]
1-[(2R,6R,11S)-9-Bromo-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4-
H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone
[0539] A solution of
2,2,2-trifluoro-1-[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-
-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (3.0 g) and
pyridinium tribromide (3.3 g) in acetic acid (2 mL) is stirred at
80.degree. C. for 2 h. After cooling to room temperature, water is
added and the resulting mixture is extracted with ethyl acetate.
The combined organic extracts are washed with water, aqueous
NaHCO.sub.3 solution, and brine. After drying (Na.sub.2SO.sub.4),
the solvent is removed and the residue is purified by
chromatography on silica gel (cyclohexane/ethyl acetate
4:1->1:1).
[0540] Yield: 2.5 g (67% of theory)
[0541] Mass spectrum (ESI.sup.+): m/z=392/394 (Br) [M+H].sup.+
[0542] The following compound is obtained analogously to Example
XLIII:
(1)
1-[(2R,6R,11R)-9-Bromo-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2-
,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone
##STR00158##
[0544] Mass spectrum (ESI.sup.+): m/z=392/394 (Br) [M+H].sup.+
Example XLIV
##STR00159##
[0545]
(2R,6R,11S)-8-Hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,-
3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile
[0546] A mixture of
(2R,6R,11S)-1-(9-bromo-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6--
methano-benzo[d]azocin-3-yl)-2,2,2-trifluoro-ethanone (0.50 g) and
copper cyanide (0.23 g) in N-methyl-pyrrolidone (2 mL) is stirred
in a microwave oven with irradiation at 180.degree. C. for 1 h.
After cooling to room temperature, water is added and the resulting
mixture is extracted with ethyl acetate. The combined organic
extracts are washed with brine and dried (Na.sub.2SO.sub.4). After
removing the solvent, the residue is purified by chromatography on
silica gel (cyclohexane/ethyl acetate 2:1->1:2).
[0547] Yield: 0.20 g (46% of theory)
[0548] Mass spectrum (ESI.sup.+): m/z=339 [M+H].sup.+
[0549] The following compound is obtained analogously to Example
XLIV:
(1)
(2R,6R,11R)-8-Hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4-
,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile
##STR00160##
[0551] Mass spectrum (ESI.sup.+): m/z=339 [M+H].sup.+
Example XLV
##STR00161##
[0552]
(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d-
]azocine-9-carbonitrile
[0553] A solution of KF (76 mg) in water (1 mL) followed by
polymethylhydrosiloxane (1.0 g) is added to a mixture of
(2R,6R,11S)-trifluoro-methanesulfonic acid
9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,-
6-methano-benzo[d]azocin-8-yl ester (0.30 g) and Pd(OAc).sub.2 (7
mg) in tetrahydrofuran (3 mL). The resulting mixture is stirred at
room temperature overnight, before 1 M aqueous NaOH solution (20
mL) is added. After stirring vigorously for 1 h, the organic phase
is separated and the aqueous phase is extracted with ethyl acetate.
The combined organic phases are washed with water and brine and
dried (MgSO.sub.4). The solvent is removed and the residue is taken
up in 4 M aqueous NaOH solution (1 mL) and methanol (3 mL) and
stirred at room temperature overnight. Then, the solution is
neutralized with 1 M hydrochloric acid, filtered, and concentrated
and the residue is purified by HPLC on reversed phase
(MeCN/water).
[0554] Yield: 0.07 g (48% of theory)
[0555] Mass spectrum (ESI.sup.+): m/z=227 [M+H].sup.+
[0556] The following compound is obtained analogously to Example
XLV:
(1)
(2R,6R,11R)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]az-
ocine-9-carbonitrile
##STR00162##
[0557] Example XLVI
##STR00163##
[0558]
1-[(2R,6S)-8-Bromo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-meth-
ano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone and
1-[(2R,6S)-10-bromo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-b-
enzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone
[0559] AlCl.sub.3 (147 mg) is added to a solution of
2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-me-
thano-benzo[d]azocin-3-yl]-ethanone (275 mg) in 1,2-dichloroethane
(10 mL). The resulting mixture is stirred at ambient temperature
for 10 min before bromine (52 .mu.L) is added. The mixture is
heated to 50.degree. C. After stirring at 50.degree. C. for 1 h,
the mixture is cooled to ambient temperature and diluted with
dichloromethane (30 mL) and water (10 mL). The resulting mixture is
stirred vigorously for 5 min and then 4 M hydrochloric acid (10 mL)
is added. The organic phase is separated and washed with 4 M
hydrochloric acid and water and dried (MgSO.sub.4). The solvent is
removed under reduced pressure to give the two title compounds in a
mixture with a further regioisomerically brominated educt.
[0560] Yield: 328 mg (95% of theory)
[0561] Mass spectrum (ESI.sup.+): m/z=390/392 (Br) [M+H].sup.+
Example XLVII
##STR00164##
[0562]
2,2,2-Trifluoro-1-[(2R,6S)-8-methanesulfonyl-6,11,11-trimethyl-1,2,-
5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone and
2,2,2-trifluoro-1-[(2R,6S)-10-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-t-
etrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
[0563] MeSO.sub.2Na (0.79 g) is added to a mixture of CuI (1.5 g)
and
1-[(2R,6S)-8-bromo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-be-
nzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone/1-[(2R,6S)-10-bromo-6,11,11-tr-
imethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifl-
uoro-ethanone (300 mg, crude product from Example XLVI) in
dimethylsulfoxide (6 mL). The resulting mixture is heated to
120.degree. C. and stirred at this temperature overnight. After
cooling to ambient temperature, the mixture is poured into a
solution of concentrated aqueous ammonia solution (20 mL) and water
(80 mL). The resulting mixture is extracted with ethyl acetate and
the combined organic extracts are washed with 2 M ammonia solution
and brine. After drying (MgSO.sub.4), the solvent is removed under
reduced pressure and the residue is purified by HPLC on reversed
phase (MeCN/water) to give the two title compounds separated.
2,2,2-Trifluoro-1-[(2R,6S)-8-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-tet-
rahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone: Yield: 150 mg
(50% of theory)
[0564] Mass spectrum (ESI.sup.+): m/z=390 [M+H].sup.+
2,2,2-Trifluoro-1-[(2R,6S)-10-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-te-
trahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone: Yield: 100
mg (33% of theory)
[0565] Mass spectrum (ESI.sup.+): m/z=390 [M+H].sup.+
Example XLVIII
##STR00165##
[0566]
2,2,2-Trifluoro-1-[(2R,6S)-6,11,11-trimethyl-8,9-dinitro-1,2,5,6-te-
trahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone
[0567] Nitric acid (0.16 mL) is added to a solution of
trifluoroacetic acid (0.65 mL) in dichloromethane (4 mL) chilled in
an ice bath (ca. 0.degree. C.). After stirring for 10 min,
2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-me-
thano-benzo[d]azocin-3-yl]-ethanone (0.50 g) in dichloromethane (5
mL) is added. The resulting solution is stirred in the cooling bath
for 2 h and then at ambient temperature overnight. The solution is
poured into ice-cold water and the resulting mixture is extracted
with dichloromethane. The combined organic extracts are washed with
aqueous NaHCO.sub.3 solution and dried (MgSO.sub.4). The solvent is
removed under reduced pressure and the residue is purified by
chromatography on silica gel (cyclohexane/ethyl acetate
1:0->9:1).
[0568] Yield: 330 mg (51% of theory)
[0569] Mass spectrum (ESI.sup.+): m/z=402 [M+H].sup.+
Example IL
##STR00166##
[0570]
1-[(2R,6S)-8,9-Diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6--
methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone
[0571] A mixture of 10% palladium on carbon (300 mg) and
2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-8,9-dinitro-1,2,5,6-tetrahyd-
ro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (330 mg) in
methanol (5 mL) is shaken under hydrogen atmosphere at room
temperature for 2 h. Then, the catalyst is separated by filtration
and the solvent is removed under reduced pressure to give the crude
title compound that is used without further purification.
[0572] Yield: 260 mg (93% of theory)
[0573] Mass spectrum (ESI.sup.+): m/z=342 [M+H].sup.+
Example L
##STR00167##
[0574]
(7R,11S)-6,7,8,9,10,11-Hexahydro-11,13,13-trimethyl-7,11-methano-py-
razino[2,3-i][3]benzazocine
[0575] Glyoxal (40% in water, 95 .mu.L) is added to
1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methan-
o-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (260 mg) dissolved
in ethanol (3 mL) and chilled in an ice bath. The cooling bath is
removed and the solution is stirred at ambient temperature
overnight. Then, the solution is concentrated and the residue is
taken up in methanol (1 mL) and treated with 4 M aqueous NaOH
solution (0.38 mL). After stirring at ambient temperature
overnight, brine is added and the resulting mixture is extracted
with ethyl acetate. The combined organic extracts are washed with
brine, dried (MgSO.sub.4), and the solvent is removed under reduced
pressure to give the crude title compound that is used without
further purification.
[0576] Yield: 204 mg
[0577] Mass spectrum (ESI.sup.+): m/z=268 [M+H].sup.+
[0578] The following compound is obtained analogously to Example
L:
(1)
(7R,11S)-6,7,8,9,10,11-Hexahydro-2,3,11,13,13-pentamethyl-7,11-methano-
-pyrazino[2,3-i][3]benzazocine
##STR00168##
[0580] Mass spectrum (ESI.sup.+): m/z=296 [M+H].sup.+
[0581] The compound is obtained by using diacetyl according to the
procedure described above.
Example LI
##STR00169##
[0582]
2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-2,10,12,12-tetra-
methyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone
[0583]
1-[(2R,6S)-8,9-Diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6--
methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (600 mg)
dissolved in glacial acetic acid is stirred at 130.degree. C. for 3
h. After cooling to ambient temperature, the solution is
concentrated under reduced pressure and the residue is taken up in
ethyl acetate. The organic solution is washed with aqueous
K.sub.2CO.sub.3 solution and brine and dried (MgSO.sub.4). The
solvent is removed under reduced pressure to give the crude title
compound as a foam-like solid.
[0584] Yield: 642 mg
[0585] Mass spectrum (ESI.sup.+): m/z=366 [M+H].sup.+
[0586] The following compound is obtained analogously to Example
LI:
(1)
2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl--
6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone
##STR00170##
[0588] Mass spectrum (ESI.sup.+): m/z=352 [M+H].sup.+
[0589] The reaction is carried out with formic acid instead of
acetic acid.
Example LII
##STR00171##
[0590]
(6R,10S)-5,6,7,8,9,10-Hexahydro-3,10,12,12-tetramethyl-6,10-methano-
-imidazo[4,5-i][3]benzazocine (I) and
(6R,10S)-5,6,7,8,9,10-hexahydro-1,10,12,12-tetramethyl-6,10-methano-imida-
zo[5,4-i][3]benzazocine (II)
[0591] Methyl iodide (69 .mu.L) is added to a mixture of
(2R,6S)-1-(8,9-imidazo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methan-
o-benzo[d]azocin-3-yl)-2,2,2-trifluoro-ethanone (300 mg) and
K.sub.2CO.sub.3 (118 mg) in N,N-dimethylformamide (2 mL). The
resulting mixture is stirred at room temperature overnight. Then,
water is added and the mixture is extracted with ethyl acetate. The
combined extracts are washed with brine and dried (MgSO.sub.4). The
solvent is removed and the residue is taken up in methanol (3 mL)
and treated with 4 M aqueous NaOH solution (0.5 mL). The solution
is stirred at room temperature overnight and then diluted with
ethyl acetate. The resulting solution is washed with water and
brine and dried (MgSO.sub.4). The solvent is removed under reduced
pressure to give the crude title compounds as a mixture.
[0592] Yield: 90 mg (39% of theory)
[0593] The following compounds are obtained analogously to Example
LII:
(1)
(6R,10S)-5,6,7,8,9,10-hexahydro-1,2,10,12,12-pentamethyl-6,10-methano--
imidazo[5,4-i][3]benzazocine
##STR00172##
[0595] Mass spectrum (ESI.sup.+): m/z=284 [M+H].sup.+
(2)
(6R,10S)-5,6,7,8,9,10-hexahydro-2,3,10,12,12-pentamethyl-6,10-methano--
imidazo[4,5-i][3]benzazocine
##STR00173##
[0597] Mass spectrum (ESI.sup.+): m/z=284 [M+H].sup.+
[0598] The two isomeric compounds (1) and (2) were obtained from
the same starting compound and separated by HPLC on reversed
phase.
Example LIII
##STR00174##
[0599] 2-Benzyl-2-aza-bicyclo[3.3.1]nonan-6-ol
[0600] Diisobutylaluminum hydride (1.5 mol/L in toluene, 21 mL) is
added to a solution of acetic acid
2-benzyl-3-oxo-2-aza-bicyclo[3.3.1]non-6-yl ester (1.50 g, for
synthesis see J. Chem. Soc. Perkin Trans. 1 1999, 1157-1162) in
toluene (30 mL) cooled to -70.degree. C. The cooling bath is
removed and the solution is stirred at ambient temperature
overnight. Then, another portion of diisobutylaluminum hydride (1.5
mol/L in toluene, 20 mL) is added and the solution is stirred for
additional 4 h at room temperature. Then, the solution is poured
into ice-cold water and the resulting mixture is extracted with
ethyl acetate. The aqueous phase is acidified using 4 M
hydrochloric acid and extracted one more time with ethyl acetate.
The combined organic extracts are dried (Na.sub.2SO.sub.4) and the
solvent is removed. The residue is purified by chromatography on
silica gel (dichloromethane/methanol 1:0->2:1).
[0601] Yield: 440 mg (36% of theory)
[0602] Mass spectrum (ESI.sup.+): m/z=232 [M+H].sup.+
Example LIV
##STR00175##
[0603] 2-Benzyl-2-aza-bicyclo[3.3.1]nonan-6-one
[0604] Dess-Martin periodinane (1.30 g) is added to a solution of
2-benzyl-2-aza-bicyclo[3.3.1]nonan-6-ol (0.60 g) in dichloromethane
(15 mL) chilled in an ice bath. The cooling bath is removed and the
solution is stirred at ambient temperature for 1 h. Then, the
solution is diluted with dichloromethane and washed with a mixture
of aqueous Na.sub.2S.sub.2O.sub.3 solution and aqueous NaHCO.sub.3
solution. The solution is dried (Na.sub.2SO.sub.4) and the solvent
is removed. The residue is purified by chromatography on silica gel
(dichloromethane/methanol 1:0->2:1).
[0605] Yield: 250 mg (42% of theory)
[0606] Mass spectrum (ESI.sup.+): m/z=230 [M+H].sup.+
Example LV
##STR00176##
[0607]
3-Benzyl-2,3,4,5,6,7-hexahydro-2,6-methano-1H-azocino[5,4-b]indole
[0608] A solution of 2-benzyl-2-aza-bicyclo[3.3.1]nonan-6-one in
acetic acid (0.24 g) is added to a solution of PhNHNH.sub.2*HCl
(173 mg) in acetic acid (4 mL) heated at reflux temperature. After
stirring at this temperature for 2 h, the solution is cooled to
room temperature and aqueous K.sub.2CO.sub.3 solution is added. The
resulting mixture is extracted with ethyl acetate, the combined
organic extracts are dried (Na.sub.2SO.sub.4), and the solvent is
removed. The residue is purified by HPLC on reversed phase
(MeCN/water).
[0609] Yield: 160 mg (49% of theory)
Example LVI
##STR00177##
[0610]
cis-4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexanecarboxylic
acid
[0611] Sodium hydride (0.22 g) is added to a solution of
cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (0.49 g)
in N,N-dimethylacetamide (5 mL) chilled in an ice bath. The cooling
bath is removed and the mixture is stirred at room temperature for
1.5 h. Then, the mixture is cooled in an ice bath and methyl iodide
(0.63 mL) is added. The cooling bath is removed and the mixture is
stirred at room temperature overnight. 1 M aqueous NaOH solution (6
mL) is added and the mixture is stirred at room temperature for
another 12 h. Then diethyl ether is added and the aqueous phase is
separated. The organic phase is extracted three times with water
and the aqueous extracts and phase are combined and acidified using
2 M aqueous KHSO.sub.4 solution. The acidic aqueous phase is
extracted with diethyl ether and the combined organic extracts are
dried (Na.sub.2SO.sub.4). The solvent is evaporated to afford the
title compound as a solid.
[0612] Yield: 0.46 mg (89% of theory)
[0613] Mass spectrum (ESI.sup.+): m/z=258 [M+H].sup.+
Example LVII
##STR00178##
[0614] cis-3-(Pyrrolidine-1-carbonyl)-cyclopentanecarboxylic
acid
[0615] A mixture of cis-cyclopentane-1,3-dicarboxylic acid (1.00
g), acetic anhydride (1.20 mL), and toluene (5 mL) is stirred at
80.degree. C. for 40 min. After cooling to room temperature, the
solution is concentrated under reduced pressure. The residue is
taken up in dichloromethane (20 mL) and the resulting solution is
filtered to remove the non-dissolving part of the residue.
Pyrrolidine (0.53 mL) is added to the filtrate and the solution is
stirred at room temperature for 30 min. Then, the solution is
concentrated under reduced pressure and the residue is dissolved in
tetrahydrofuran and treated with Dowex H.sup.+ resin. The mixture
is filtered and the filrate is concentrated to afford the title
compopund as an oil.
[0616] Yield: 1.34 g (quantitative)
[0617] The following compound is obtained analogously to Example
LVII:
(1) cis-Cyclopentane-1,3-dicarboxylic acid monomethyl ester
##STR00179##
[0619] Methanol is used to open up the intermediate anhydride.
Preparation of the End Compounds:
Procedure A (Described for Example 1, Table 3)
##STR00180##
[0620]
[(2S)-2,3-Dihydro-benzo[1,4]dioxin-2-yl]-[(2R,6R,11R)-8-hydroxy-6,1-
1-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanon-
e
[0621] Carbonyldiimidazole (0.47 g) is added to a solution of
(S)-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (0.63 g) in
dichloromethane (6 mL). The resulting solution is stirred at room
temperature for 1 h before
(2R,6R,11R)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azoci-
n-10-ol is added. The solution is further stirred at room
temperature overnight. Then, dichloromethane (30 mL) is added and
the resulting solution is washed with water. After drying
(Na.sub.2SO.sub.4), the solvent is evaporated to give the product
as a white foam-like solid.
[0622] Yield: 0.70 g (66% of theory)
[0623] Mass spectrum (ESI.sup.+): m/z=380 [M+H].sup.+
[0624] The product is additionally purified by HPLC on reversed
phase (H.sub.2O/MeCN) in case the purity after the procedure
described above is insufficient.
Procedure B (Described for Example 3, Table 3)
##STR00181##
[0626]
Cyclopentyl-[(2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydr-
o-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
[0627] 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (0.27 g; alternatively
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate may be used) is added to a solution of
cyclopentanecarboxylic acid (100 mg) and ethyldiisopropylamine (0.2
mL) in N,N-dimethylformamide (10 mL). The resulting solution is
stirred at ambient temperature for 15 min before
(2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-be-
nzo[d]azocine (0.20 g) is added. After stirring the solution
overnight, ethyl acetate is added and the resulting mixture is
washed with aqueous Na.sub.2CO.sub.3 solution and dried
(Na.sub.2SO.sub.4). After evaporation of the solvent under reduced
pressure, the product is obtained as a yellow oil.
[0628] Yield: 0.27 g (99% of theory)
[0629] Mass spectrum (ESI.sup.+): m/z=342 [M+H].sup.+
[0630] The product is additionally purified by HPLC on reversed
phase (H.sub.2O/MeCN) in case the purity after the procedure
described above is insufficient.
Procedure C (Described for Example 4, Table 3)
##STR00182##
[0632]
Cyclopentyl-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydr-
o-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
[0633] Boron tribromide (2.8 mL) is added to a solution of
cyclopentyl-[(2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2-
,6-methano-benzo[d]azocin-3-yl]-methanone (280 g) in dichlormethane
(10 mL). The resulting solution is stirred at ambient temperature
for 2 h and then quenched by the addition of water. The organic
phase is separated, washed with water and dried (Na.sub.2SO.sub.4).
Evaporation of the solvent under reduced pressure affords the
product.
[0634] Yield: 175 mg (65% of theory)
[0635] Mass spectrum (ESI.sup.+): m/z=328 [M+H].sup.+
[0636] The product is additionally purified by HPLC on reversed
phase (H.sub.2O/MeCN) in case the purity is insufficient after the
procedure described above.
Procedure D (Described for Example 5, Table 3)
##STR00183##
[0637]
Cyclopentyl-[(2R,6R,11R)-8-methoxy-6,11-dimethyl-7,9-dinitro-1,2,5,-
6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
[0638] Cyclopentanecarbonyl chloride (0.12 g) is added to the
trifluoroacetic acid salt of
(2R,6R,11R)-8-methoxy-6,11-dimethyl-7,9-dinitro-1,2,3,4,5,6-hexahydro-2,6-
-methano-benzo[d]azocine (0.43 g) and triethylamine (0.31 mL)
dissolved in dichloromethane (10 mL). The resulting solution is
stirred at room temperature overnight. Then, aqueous
Na.sub.2CO.sub.3 solution is added and the resulting mixture is
extracted with dichloromethane. The combined extracts are washed
with water and dried (Na.sub.2SO.sub.4) and the solvent is
evaporated. The residue is purified by HPLC on reversed phase
(MeCN/H.sub.2O) to give the product as a white solid.
[0639] Yield: 0.25 g (61% of theory)
[0640] Mass spectrum (ESI.sup.+): m/z=418 [M+H].sup.+
Procedure E (Described for Example 7, Table 3)
##STR00184##
[0641]
Cyclopentyl-[(2R,6R)-8-methoxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-m-
ethano-benzo[d]azocin-3-yl]-methanone
[0642] Sodium hydride (0.01 g) is added to a solution of
cyclopentyl-[(2R,6R)-8-hydroxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocin-3-yl]-methanone (0.10 g) in tetrahydrofuran (6 mL;
alternatively N,N-dimethylformamide may be used). The mixture is
stirred for 30 min at room temperature before methyl iodide (25
.mu.L) is added. The resulting solution is stirred at room
temperature overnight. Then, water is added and the resulting
mixture is extracted with dichloromethane. The combined extracts
are dried (Na.sub.2SO.sub.4) and the solvent is evaporated. The
residue is purified by chromatography on silica gel
(cyclohexane/ethyl acetate).
[0643] Yield: 0.10 g (97% of theory)
[0644] Mass spectrum (ESI.sup.+): m/z=314 [M+H].sup.+
Procedure F (Described for Example 30, Table 3)
##STR00185##
[0645]
[(S)-2,3-Dihydro-benzo[1,4]dioxin-2-yl]-[(2R,6R,11R)-6,11-dimethyl--
1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
[0646] 10% Pd/C (0.10 g) is added to a solution of
(2R,6R,11R)-trifluoro-methanesulfonic acid
3-[(S)-2,3-dihydro-benzo[1,4]dioxine-2-carbonyl]-6,11-dimethyl-1,2,3,4,5,-
6-hexahydro-2,6-methano-benzo[d]azocin-8-yl ester (0.50 g) in
methanol (15 mL) and ethyl acetate (25 mL). The resulting mixture
is shaken under hydrogen atmosphere (50 psi) at room temperature
overnight. Then, the catalyst is separated by filtration and the
filtrate is concentrated under reduced pressure. The residue is
purified by HPLC on reversed phase (MeCN/H.sub.2O) to give the
product as a colorless gum-like solid.
[0647] Yield: 0.08 g (23% of theory)
[0648] Mass spectrum (ESI.sup.+): m/z=364 [M+H].sup.+
Procedure G (Described for Example 52, Table 3)
##STR00186##
[0649]
cis-4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2-
,6-methano-benzo[d]azocine-3-carbonyl]-cyclohexane carboxylic
acid
[0650] 4 M aqueous NaOH solution (3.5 mL) is added to a solution of
cis-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-met-
hano-benzo[d]azocine-3-carbonyl]-cyclohexane carboxylic acid methyl
ester (1.2 g) in methanol (20 mL). The resulting solution is
stirred at room temperature overnight. Then, 4 M hydrochloric acid
is added, the resulting mixture is extratced with ethyl acetate,
and the combined extratcs are dried (Na.sub.2SO.sub.4). After
removal of the solvent, the residue is triturated with a mixture of
acetonitrile and ether.
[0651] Yield: 0.83 g (71% of theory)
[0652] Mass spectrum (ESI.sup.+): m/z=386 [M+H].sup.+
Procedure H (Described for Example 78, Table 3)
##STR00187##
[0653]
[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-met-
hano-benzo[d]azocin-3-yl]-pyrrolidin-2-yl-methanone
[0654] A solution of
2-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carbonyl]-pyrrolidine-1-carboxylic acid
tert-butyl ester (10.9 mg) in trifluoroacetic acid (2 mL) is
stirred at ambient temperature for 2 h. Then, the solution is
concentrated under reduced pressure to give the trifluoroacetic
acid salt of the title compound.
[0655] Yield: 8.7 mg (77% of theory)
[0656] Mass spectrum (ESI.sup.+): m/z=329 [M+H].sup.+
Procedure I (described for Example 93, Table 3)
##STR00188##
[(1R,3R)-3-Benzylamino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-
-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
[0657] Benzyl bromide (16 .mu.L) is added to a solution of
[(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5-
,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (50 mg)
and ethyldiisopropylamine (68 .mu.L) in acetonitrile (1 mL). The
resulting solution is stirred at 70.degree. C. for 3 h. After
cooling to room temperature, the solution is concentrated under
reduced pressure and the residue is purified by HPLC on reversed
phase (MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give the trifluoroacetic
acid salt of the title compound.
[0658] Yield: 28 mg (50% of theory)
[0659] Mass spectrum (ESI.sup.+): m/z=433 [M+H].sup.+
Procedure J (Described for Example 101, Table 3)
##STR00189##
[0660]
N-{(1R,3R)-3-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahyd-
ro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclopentyl}-benzenesulfonam-
ide
[0661] Benzenesulfonyl chloride (41 mg) is added to a solution of
[(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5-
,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (80 mg)
and triethylamine (120 .mu.L) in dichloromethane (1 mL). The
resulting solution is stirred at room temperature overnight and
then concentrated under reduced pressure. The residue is purified
by HPLC on reversed phase (MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give
the title compound.
[0662] Yield: 36 mg (35% of theory)
[0663] Mass spectrum (ESI.sup.+): m/z=483 [M+H].sup.+
Procedure K (Described for Example 104, Table 3)
##STR00190##
[0664]
1-{(1R,3R)-3-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahyd-
ro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclopentyl}-3-phenyl-urea
[0665] Aniline (19 .mu.L) and triethylamine (100 .mu.L) dissolved
in dichloromethane (0.5 mL) are added to a solution of triphosgene
(19 mg) in dichloromethane (0.5 mL) chilled in an ice bath. After
stirring the solution for 30 min,
[(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5-
,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (80 mg)
and triethylamine (30 .mu.L) dissolved in dichloromethane (1 mL)
are added. The resulting solution is stirred in the cooling bath
for 15 min and then at room temperature for 2 h. The solution is
concentrated under reduced pressure and the residue is purified by
HPLC on reversed phase (MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give
the title compound.
[0666] Yield: 7 mg (5% of theory)
[0667] Mass spectrum (ESI.sup.+): m/z=462 [M+H].sup.+
Procedure L (Described for Example 105, Table 3)
##STR00191##
[0668]
[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-met-
hano-benzo[d]azocin-3-yl]-[(1R,3R)-3-isopropylamino-cyclopentyl]-methanone
[0669] Sodium triacetoxyborohydride (56 mg) is added to a solution
of
[(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5-
,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (50
mg), acetone (9 mg), trimethyl orthoformate (28 mg), and acetic
acid (23 .mu.L) in N,N-dimethylformamide (1 mL). The resulting
mixture is stirred at room temperature for 3 h. The solution is
concentrated under reduced pressure and the residue is purified by
HPLC on reversed phase (MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give
the trifluoroacetic acid salt of the title compound.
[0670] Yield: 44 mg (66% of theory)
[0671] Mass spectrum (ESI.sup.+): m/z=385 [M+H].sup.+
Procedure M (Described for Example 117, Table 3)
##STR00192##
[0672]
1-tert-Butyl-3-{(1R,3R)-3-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2-
,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclopentyl}-ur-
ea
[0673] tert-Butylisocyanate (30 mg) is added to a solution of
[(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5-
,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (100
mg) and ethyldiisopropylamine (120 .mu.L) in N,N-dimethylformamide
(2 mL). The resulting solution is stirred at 40.degree. C.
overnight. Then, the solution is concentrated under reduced
pressure and the residue is purified by HPLC on reversed phase
(MeCN/H.sub.2O/F.sub.3CCO.sub.2H) to give the title compound.
[0674] Yield: 7 mg (5% of theory)
[0675] Mass spectrum (ESI.sup.+): m/z=462 [M+H].sup.+
Procedure N (Described for Example 128, Table 3)
##STR00193##
[0676]
4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-m-
ethano-benzo[d]azocine-3-carbonyl)-cyclohexanecarboxylic acid ethyl
ester
[0677] SOCl.sub.2 (5 mL) is added dropwise to a suspension of
4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-
-benzo[d]azocine-3-carbonyl]-cyclohexanecarboxylic acid (100 mg) in
ethanol (5 mL) cooled to -20.degree. C. Then, the cooling bath is
removed and the resulting mixture is stirred at ambient temperature
overnight. The solution is concentrated under reduced pressure and
the residue is triturated with acetone and dried.
[0678] Yield: 61 mg (58% of theory)
[0679] Mass spectrum (ESI.sup.+): m/z=414 [M+H].sup.+
Procedure O (Described for Example 180, Table 3)
##STR00194##
[0680]
cis-4-[(2R,6S)-9-tert-Butyl-10-hydroxy-6,11,11-trimethyl-1,2,5,6-te-
trahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclohexanecarboxylic
acid
[0681] SOCl.sub.2 (1 mL) is added dropwise to a solution of
cis-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-met-
hano-benzo[d]azocine-3-carbonyl]-cyclohexane carboxylic acid (100
mg) in tert-butanol (5 mL) cooled to -10.degree. C. Then, the
cooling bath is removed and the resulting solution is stirred at
ambient temperature overnight before another portion of SOCl.sub.2
(1 mL) is added. After stirring for additional 12 h more SOCl.sub.2
(2 mL) is added and the solution is heated to 50.degree. C. The
solution is stirred at this temperature for 48 h before HCl in
1,4-dioxane (1 mL) is added. The resulting solution is stirred at
reflux temperature overnight and then treated with concentrated
H.sub.2SO.sub.4 (3 mL). After stirring at reflux temperature for
additional 3 h, the solution is cooled to ambient temperature and
concentrated under reduced pressure. The residue is treated with
water and the precipitate is separated by filtration. The
precipitate is taken up in ethyl acetate and washed with water and
dried (MgSO.sub.4). After removing the solvent, the residue is
purified by HPLC (water/MeCN/F.sub.3CCO.sub.2H).
[0682] Yield: 12 mg (11% of theory)
[0683] Mass spectrum (ESI.sup.+): m/z=442 [M+H].sup.+
Procedure P (Described for Example 195, Table 3)
##STR00195##
[0684]
[cis-3-(1-Hydroxy-1-methyl-ethyl)-cyclohexyl]-[(2R,6S)-6,11,11-trim-
ethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
(diastereomeric mixture derived from the two cis-configured
enantiomers of the cyclohexane moiety)
[0685] MeMgBr (1.4 M in tetrahydrofuran/toluene, 1.3 mL) is added
dropwise to a solution of
cis-3-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[-
d]azocine-3-carbonyl]-cyclohexanecarboxylic acid methyl ester (0.24
g, diastereomeric mixture derived from the two cis-configured
enantiomers of the cyclohexane moiety) in tetrahydrofuran (2 mL)
chilled in an ice bath. The solution is stirred with cooling for 2
h and then the reaction is quenched by the addition of aqueous
NH.sub.4Cl solution. The resulting mixture is extracted with
tert-butyl methyl ether and the combined extracts are dried
(MgSO.sub.4). The solvent is evaporated to give the title compound
as a foam-like solid.
[0686] Yield: 0.20 g (84% of theory)
[0687] Mass spectrum (ESI.sup.+): m/z=384 [M+H].sup.+
Procedure Q (Described for Example 204, Table 3)
##STR00196##
[0688]
(cis-3-Hydroxymethyl-cyclohexyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-
-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone
(diastereomeric mixture derived from the two cis-configured
enantiomers of the cyclohexane moiety)
[0689] LiAlH.sub.4 (1 M in tetrahydrofuran, 0.43 mL) is added
dropwise to a solution of
cis-3-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[-
d]azocine-3-carbonyl]-cyclohexanecarboxylic acid methyl ester (0.30
g, diastereomeric mixture derived from the two cis-configured
enantiomers of the cyclohexane moiety) in tetrahydrofuran (3 mL)
cooled to -10.degree. C. The solution is stirred with cooling for 2
h and then the reaction is quenched by the addition of water. The
resulting mixture is extracted with tert-butyl methyl ether and the
combined extracts are are washed with brine and dried (MgSO.sub.4).
The solvent is evaporated to afford the title compound as a
diastereomeric mixture.
[0690] Yield: 0.27 g (96% of theory)
[0691] Mass spectrum (ESI.sup.+): m/z=356 [M+H].sup.+
Procedure R (Described for Example 203, Table 3)
##STR00197##
[0692] (4-Hydroxy-4-trifluoromethyl-cyclohexyl)-[(2R,6
S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-y-
l]-methanone (diastereomeric mixture derived from the two
cyclohexane diastereomers)
[0693] (Trifluoromethyl)trimethylsilane (2 M in tetrahydrofuran,
0.42 mL) is added to a mixture of
4-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]az-
ocine-3-carbonyl]-cyclohexanone (0.26 g) and CsF (12 mg) in
tetrahydrofuran (5 mL) cooled to -5.degree. C. The mixture is
stirred at -5.degree. C. for 1.5 h, before 1 M hydrochloric acid (5
mL) is added. The resulting mixture is stirred at room temperature
overnight. The reaction mixture is concentrated and the residue is
purified by HPLC on reversed phase (acetonitrile/water) to afford
the title compound as a diastereomeric mixture.
[0694] Yield: 0.12 g (38% of theory)
[0695] Mass spectrum (ESI.sup.+): m/z=410 [M+H].sup.+
TABLE-US-00004 TABLE 3 Compounds prepared in analogy to the
examples described above Prepared in Example analogy to No.
Chemical Name/Structure/Remarks Procedure Characterization 1
##STR00198## A Mass spectrum (ESI.sup.+): m/z = 380 [M + H].sup.+ 2
##STR00199## A Mass spectrum (ESI.sup.+): m/z = 380 [M + H].sup.+ 3
##STR00200## B Mass spectrum (ESI.sup.+): m/z = 342 [M + H].sup.+ 4
##STR00201## C Mass spectrum (ESI.sup.+): m/z = 328 [M + H].sup.+ 5
##STR00202## D Mass spectrum (ESI.sup.+): m/z = 418 [M + H].sup.+ 6
##STR00203## C Mass spectrum (ESI.sup.+): m/z = 404 [M + H].sup.+ 7
##STR00204## D Mass spectrum (ESI.sup.+): m/z = 328 [M + H].sup.+ 8
##STR00205## D Mass spectrum (ESI.sup.+): m/z = 314 [M + H].sup.+ 9
##STR00206## D Mass spectrum (ESI.sup.+): m/z = 300 [M + H].sup.+
10 ##STR00207## E Mass spectrum (ESI.sup.+): m/z = 300 [M +
H].sup.+ 11 ##STR00208## B Mass spectrum (ESI.sup.+): m/z =
382/384/386 (2Cl) [M + H].sup.+ 12 ##STR00209## B Mass spectrum
(ESI.sup.+): m/z = 348/350 (Cl) [M + H].sup.+ 13 ##STR00210## B
Mass spectrum (ESI.sup.+): m/z = 334/336 (Cl) [M + H].sup.+ 14
##STR00211## B Mass spectrum (ESI.sup.+): m/z = 372 [M + H].sup.+
15 ##STR00212## B Mass spectrum (ESI.sup.+): m/z = 354 [M +
H].sup.+ 16 ##STR00213## B Mass spectrum (ESI.sup.+): m/z = 386 [M
+ H].sup.+ 17 ##STR00214## B Mass spectrum (ESI.sup.+): m/z = 425
[M + H].sup.+ 18 ##STR00215## B Mass spectrum (ESI.sup.+): m/z =
400 [M + H].sup.+ 19 ##STR00216## B Mass spectrum (ESI.sup.+): m/z
= 378 [M + H].sup.+ 20 ##STR00217## B Mass spectrum (ESI.sup.+):
m/z = 387 [M - tertBu + 2H].sup.+ 21 ##STR00218## B Mass spectrum
(ESI.sup.+): m/z = 372 [M + H].sup.+ 22 ##STR00219## B Mass
spectrum (ESI.sup.+): m/z = 404 [M + H].sup.+ 23 ##STR00220## B
Mass spectrum (ESI.sup.+): m/z = 356 [M + H].sup.+ 24 ##STR00221##
B Mass spectrum (ESI.sup.+): m/z = 352 [M + H].sup.+ 25
##STR00222## B Mass spectrum (ESI.sup.+): m/z = 400 [M + H].sup.+
26 ##STR00223## A Mass spectrum (ESI.sup.+): m/z = 404 [M +
H].sup.+ 27 ##STR00224## E Mass spectrum (ESI.sup.+): m/z = 408 [M
+ H].sup.+ 28 ##STR00225## E Mass spectrum (ESI.sup.+): m/z = 470
[M + H].sup.+ 29 ##STR00226## E Mass spectrum (ESI.sup.+): m/z =
420 [M + H].sup.+ 30 ##STR00227## F Mass spectrum (ESI.sup.+): m/z
= 364 [M + H].sup.+ 31 ##STR00228## E Mass spectrum (ESI.sup.+):
m/z = 394 [M + H].sup.+ 32 ##STR00229## E Mass spectrum
(ESI.sup.+): m/z = 408 [M + H].sup.+ 33 ##STR00230## E Mass
spectrum (ESI.sup.+): m/z = 470 [M + H].sup.+ 34 ##STR00231## F
Mass spectrum (ESI.sup.+): m/z = 364 [M + H].sup.+ 35 ##STR00232##
A Mass spectrum (ESI.sup.+): m/z = 380 [M + H].sup.+ 36
##STR00233## E Mass spectrum (ESI.sup.+): m/z = 394 [M + H].sup.+
37 ##STR00234## B Mass spectrum (ESI.sup.+): m/z = 356 [M +
H].sup.+ 38 ##STR00235## B Mass spectrum (ESI.sup.+): m/z = 356 [M
+ H].sup.+ 39 ##STR00236## B Mass spectrum (ESI.sup.+): m/z = 358
[M + H].sup.+ 40 ##STR00237## B Mass spectrum (ESI.sup.+): m/z =
368 [M + H].sup.+ 41 ##STR00238## B Mass spectrum (ESI.sup.+): m/z
= 384 [M + H].sup.+ 42 ##STR00239## B Mass spectrum (ESI.sup.+):
m/z = 358 [M + H].sup.+ 43 ##STR00240## B Mass spectrum
(ESI.sup.+): m/z = 400 [M + H].sup.+ 44 ##STR00241## B Mass
spectrum (ESI.sup.+): m/z = 410 [M + H].sup.+ 45 ##STR00242## B
Mass spectrum (ESI.sup.+): m/z = 372 [M + H].sup.+ 46 ##STR00243##
B Mass spectrum (ESI.sup.+): m/z = 400 [M + H].sup.+ 47
##STR00244## B Mass spectrum (ESI.sup.+): m/z = 384 [M + H].sup.+
48 ##STR00245## B Mass spectrum (ESI.sup.+): m/z = 400 [M +
H].sup.+ 49 ##STR00246## B Mass spectrum (ESI.sup.+): m/z = 394 [M
+ H].sup.+ 50 ##STR00247## G Mass spectrum (ESI.sup.+): m/z = 386
[M + H].sup.+ 51 ##STR00248## B Mass spectrum (ESI.sup.+): m/z =
352 [M + H].sup.+ 52 ##STR00249## G Mass spectrum (ESI.sup.+): m/z
= 386 [M + H].sup.+ 53 ##STR00250## B Mass spectrum (ESI.sup.+):
m/z = 433 [M + H].sup.+ 54 ##STR00251## B Mass spectrum
(ESI.sup.+): m/z = 429 [M + H].sup.+ 55 ##STR00252## B Mass
spectrum (ESI.sup.+): m/z = 371 [M + H].sup.+ 56 ##STR00253## B
Mass spectrum (ESI.sup.+): m/z = 382 [M + H].sup.+ 57 ##STR00254##
B Mass spectrum (ESI.sup.+): m/z = 396 [M + H].sup.+ 58
##STR00255## B Mass spectrum (ESI.sup.+): m/z = 357 [M + H].sup.+
59 ##STR00256## B Mass spectrum (ESI.sup.+): m/z = 461 [M +
H].sup.+ 60 ##STR00257## B Mass spectrum (ESI.sup.+): m/z = 433 [M
+ H].sup.+ 61 ##STR00258## B Mass spectrum (ESI.sup.+): m/z = 433
[M + H].sup.+ 62 ##STR00259## B Mass spectrum (ESI.sup.+): m/z =
477 [M + H].sup.+ 63 ##STR00260## B Mass spectrum (ESI.sup.+): m/z
= 411 [M + H].sup.+ 64 ##STR00261## B Mass spectrum (ESI.sup.+):
m/z = 429 [M + H].sup.+ 65 ##STR00262## B Mass spectrum
(ESI.sup.+): m/z = 357 [M + H].sup.+ 66 ##STR00263## B Mass
spectrum (ESI.sup.+): m/z = 357 [M + H].sup.+ 67 ##STR00264## B
Mass spectrum (ESI.sup.+): m/z = 419 [M + H].sup.+ 68 ##STR00265##
B Mass spectrum (ESI.sup.+): m/z = 385 [M + H].sup.+ 69
##STR00266## B Mass spectrum (ESI.sup.+): m/z = 357 [M + H].sup.+
70 ##STR00267## B Mass spectrum (ESI.sup.+): m/z = 343 [M +
H].sup.+ 71 ##STR00268## B Mass spectrum (ESI.sup.+): m/z = 419 [M
+ H].sup.+ 72 ##STR00269## B Mass spectrum (ESI.sup.+): m/z = 443
[M + H].sup.+ 73 ##STR00270## B Mass spectrum (ESI.sup.+): m/z =
447 [M + H].sup.+ 74 ##STR00271## B Mass spectrum (ESI.sup.+): m/z
= 436 [M + H].sup.+ 75 ##STR00272## B Mass spectrum (ESI.sup.+):
m/z = 343 [M + H].sup.+ 76 ##STR00273## B Mass spectrum
(ESI.sup.+): m/z = 419 [M + H].sup.+ 77 ##STR00274## B Mass
spectrum (ESI.sup.+): m/z = 419 [M + H].sup.+ 78 ##STR00275## H
Mass spectrum (ESI.sup.+): m/z = 329 [M + H].sup.+ 79 ##STR00276##
H Mass spectrum (ESI.sup.+): m/z = 343 [M + H].sup.+ 80
##STR00277## H Mass spectrum (ESI.sup.+): m/z = 329 [M + H].sup.+
81 ##STR00278## H Mass spectrum (ESI.sup.+): m/z = 341 [M +
H].sup.+ 82 ##STR00279## H Mass spectrum (ESI.sup.+): m/z = 341 [M
+ H].sup.+ 83 ##STR00280## H Mass spectrum (ESI.sup.+): m/z = 343
[M + H].sup.+ 84 ##STR00281## B Mass spectrum (ESI.sup.+): m/z =
385 [M + H].sup.+ 85 ##STR00282## B Mass spectrum (ESI.sup.+): m/z
= 399 [M + H].sup.+ 86 ##STR00283## B Mass spectrum (ESI.sup.+):
m/z = 413 [M + H].sup.+ 87 ##STR00284## B Mass spectrum
(ESI.sup.+): m/z = 427 [M + H].sup.+ 88 ##STR00285## B Mass
spectrum (ESI.sup.+): m/z = 439 [M + H].sup.+ 89 ##STR00286## B
Mass spectrum (ESI.sup.+): m/z = 441 [M + H].sup.+ 90 ##STR00287##
B Mass spectrum (ESI.sup.+): m/z = 461 [M + H].sup.+ 91
##STR00288## B Mass spectrum (ESI.sup.+): m/z = 475 [M + H].sup.+
92 ##STR00289## B Mass spectrum (ESI.sup.+): m/z = 441 [M +
H].sup.+ 93 ##STR00290## I Mass spectrum (ESI.sup.+): m/z = 433 [M
+ H].sup.+ 94 ##STR00291## B Mass spectrum (ESI.sup.+): m/z = 425
[M + H].sup.+ 95 ##STR00292## B Mass spectrum (ESI.sup.+): m/z =
427 [M + H].sup.+ 96 ##STR00293## B -- 97 ##STR00294## H Mass
spectrum (ESI.sup.+): m/z = 343 [M + H].sup.+ 98 ##STR00295## B
Mass spectrum (ESI.sup.+): m/z = 385 [M + H].sup.+ 99 ##STR00296##
B Mass spectrum (ESI.sup.+): m/z = 413 [M + H].sup.+ 100
##STR00297## B Mass spectrum (ESI.sup.+): m/z = 461 [M + H].sup.+
101 ##STR00298## J Mass spectrum (ESI.sup.+): m/z = 483 [M +
H].sup.+ 102 ##STR00299## J Mass spectrum (ESI.sup.+): m/z = 421 [M
+ H].sup.+ 103 ##STR00300## B Mass spectrum (ESI.sup.+): m/z = 399
[M + H].sup.+ 104 ##STR00301## K Mass spectrum (ESI.sup.+): m/z =
462 [M + H].sup.+ 105 ##STR00302## L Mass spectrum (ESI.sup.+): m/z
= 385 [M + H].sup.+ 106 ##STR00303## B Mass spectrum (ESI.sup.+):
m/z = 385 [M + H].sup.+ 107 ##STR00304## B Mass spectrum
(ESI.sup.+): m/z = 399 [M + H].sup.+ 108 ##STR00305## B Mass
spectrum (ESI.sup.+): m/z = 447 [M + H].sup.+ 109 ##STR00306## B
Mass spectrum (ESI.sup.+): m/z = 413 [M + H].sup.+ 110 ##STR00307##
B Mass spectrum (ESI.sup.+): m/z = 399 [M + H].sup.+ 111
##STR00308## B Mass spectrum (ESI.sup.+): m/z = 385 [M + H].sup.+
112 ##STR00309## J Mass spectrum (ESI.sup.+): m/z = 421 [M +
H].sup.+ 113 ##STR00310## J Mass spectrum (ESI.sup.+): m/z = 483 [M
+ H].sup.+ 114 ##STR00311## J Mass spectrum (ESI.sup.+): m/z = 407
[M + H].sup.+ 115 ##STR00312## J Mass spectrum (ESI.sup.+): m/z =
469 [M + H].sup.+ 116 ##STR00313## D Mass spectrum (ESI.sup.+): m/z
= 412 [M + H].sup.+ 117 ##STR00314## M Mass spectrum (ESI.sup.+):
m/z = 442 [M + H].sup.+ 118 ##STR00315## B Mass spectrum
(ESI.sup.+): m/z = 392 [M + H].sup.+ 119 ##STR00316## M Mass
spectrum (ESI.sup.+): m/z = 462 [M + H].sup.+ 120 ##STR00317## M
Mass spectrum (ESI.sup.+): m/z = 400 [M + H].sup.+
121 ##STR00318## M Mass spectrum (ESI.sup.+): m/z = 448 [M +
H].sup.+ 122 ##STR00319## M Mass spectrum (ESI.sup.+): m/z = 414 [M
+ H].sup.+ 123 ##STR00320## L Mass spectrum (ESI.sup.+): m/z = 385
[M + H].sup.+ 124 ##STR00321## L Mass spectrum (ESI.sup.+): m/z =
413 [M + H].sup.+ 125 ##STR00322## I Mass spectrum (ESI.sup.+): m/z
= 433 [M + H].sup.+ 126 ##STR00323## L Mass spectrum (ESI.sup.+):
m/z = 399 [M + H].sup.+ 127 ##STR00324## L Mass spectrum
(ESI.sup.+): m/z = 371 [M + H].sup.+ 128 ##STR00325## N Mass
spectrum (ESI.sup.+): m/z = 414 [M + H].sup.+ 129 ##STR00326## B
Mass spectrum (ESI.sup.+): m/z = 371 [M + H].sup.+ 130 ##STR00327##
B Mass spectrum (ESI.sup.+): m/z = 399 [M + H].sup.+ 131
##STR00328## B Mass spectrum (ESI.sup.+): m/z = 399 [M + H].sup.+
132 ##STR00329## B Mass spectrum (ESI.sup.+): m/z = 413 [M +
H].sup.+ 133 ##STR00330## N Mass spectrum (ESI.sup.+): m/z = 418 [M
+ H].sup.+ 134 ##STR00331## B Mass spectrum (ESI.sup.+): m/z = 385
[M + H].sup.+ 135 ##STR00332## B Mass spectrum (ESI.sup.+): m/z =
385 [M + H].sup.+ 136 ##STR00333## M Mass spectrum (ESI.sup.+): m/z
= 462 [M + H].sup.+ 137 ##STR00334## M Mass spectrum (ESI.sup.+):
m/z = 448 [M + H].sup.+ 138 ##STR00335## M Mass spectrum
(ESI.sup.+): m/z = 414 [M + H].sup.+ 139 ##STR00336## M Mass
spectrum (ESI.sup.+): m/z = 400 [M + H].sup.+ 140 ##STR00337## J
Mass spectrum (ESI.sup.+): m/z = 483 [M + H].sup.+ 141 ##STR00338##
J Mass spectrum (ESI.sup.+): m/z = 421 [M + H].sup.+ 142
##STR00339## J Mass spectrum (ESI.sup.+): m/z = 407 [M + H].sup.+
143 ##STR00340## J Mass spectrum (ESI.sup.+): m/z = 501 [M +
H].sup.+ 144 ##STR00341## J Mass spectrum (ESI.sup.+): m/z = 497 [M
+ H].sup.+ 145 ##STR00342## J Mass spectrum (ESI.sup.+): m/z = 513
[M + H].sup.+ 146 ##STR00343## J Mass spectrum (ESI.sup.+): m/z =
447 [M + H].sup.+ 147 ##STR00344## J Mass spectrum (ESI.sup.+): m/z
= 511 [M + H].sup.+ 148 ##STR00345## J Mass spectrum (ESI.sup.+):
m/z = 513 [M + H].sup.+ 149 ##STR00346## J Mass spectrum
(ESI.sup.+): m/z = 501 [M + H].sup.+ 150 ##STR00347## J Mass
spectrum (ESI.sup.+): m/z = 515 [M + H].sup.+ 151 ##STR00348## J
Mass spectrum (ESI.sup.+): m/z = 497 [M + H].sup.+ 152 ##STR00349##
J Mass spectrum (ESI.sup.+): m/z = 473 [M + H].sup.+ 153
##STR00350## J Mass spectrum (ESI.sup.+): m/z = 489 [M + H].sup.+
154 ##STR00351## J Mass spectrum (ESI.sup.+): m/z = 513 [M +
H].sup.+ 155 ##STR00352## J Mass spectrum (ESI.sup.+): m/z = 501 [M
+ H].sup.+ 156 ##STR00353## J Mass spectrum (ESI.sup.+): m/z = 487
[M + H].sup.+ 157 ##STR00354## J Mass spectrum (ESI.sup.+): m/z =
515 [M + H].sup.+ 158 ##STR00355## J Mass spectrum (ESI.sup.+): m/z
= 484 [M + H].sup.+ 159 ##STR00356## J Mass spectrum (ESI.sup.+):
m/z = 449 [M + H].sup.+ 160 ##STR00357## J Mass spectrum
(ESI.sup.+): m/z = 449 [M + H].sup.+ 161 ##STR00358## J Mass
spectrum (ESI.sup.+): m/z = 497 [M + H].sup.+ 162 ##STR00359## J
Mass spectrum (ESI.sup.+): m/z = 435 [M + H].sup.+ 163 ##STR00360##
J Mass spectrum (ESI.sup.+): m/z = 497 [M + H].sup.+ 164
##STR00361## J Mass spectrum (ESI.sup.+): m/z = 489 [M + H].sup.+
165 ##STR00362## J Mass spectrum (ESI.sup.+): m/z = 469 [M +
H].sup.+ 166 ##STR00363## B Mass spectrum (ESI.sup.+): m/z = 427 [M
+ H].sup.+ 167 ##STR00364## B Mass spectrum (ESI.sup.+): m/z = 461
[M + H].sup.+ 168 ##STR00365## B Mass spectrum (ESI.sup.+): m/z =
399 [M + H].sup.+ 169 ##STR00366## B Mass spectrum (ESI.sup.+): m/z
= 413 [M + H].sup.+ 170 ##STR00367## B Mass spectrum (ESI.sup.+):
m/z = 427 [M + H].sup.+ 171 ##STR00368## B Mass spectrum
(ESI.sup.+): m/z = 475 [M + H].sup.+ 172 ##STR00369## B Mass
spectrum (ESI.sup.+): m/z = 441 [M + H].sup.+ 173 ##STR00370## B
Mass spectrum (ESI.sup.+): m/z = 441 [M + H].sup.+ 174 ##STR00371##
B Mass spectrum (ESI.sup.+): m/z = 394 [M + H].sup.+ 175
##STR00372## B Mass spectrum (ESI.sup.+): m/z = 352 [M + H].sup.+
176 ##STR00373## B Mass spectrum (ESI.sup.+): m/z = 376 [M +
H].sup.+ 177 ##STR00374## B Mass spectrum (ESI.sup.+): m/z = 342 [M
+ H].sup.+ 178 ##STR00375## B Mass spectrum (ESI.sup.+): m/z = 376
[M + H].sup.+ 179 ##STR00376## B Mass spectrum (ESI.sup.+): m/z =
376 [M + H].sup.+ 180 ##STR00377## O Mass spectrum (ESI.sup.+): m/z
= 442 [M + H].sup.+ 181 ##STR00378## B Mass spectrum (ESI.sup.+):
m/z = 441 [M + H].sup.+ 182 ##STR00379## B Mass spectrum
(ESI.sup.+): m/z = 489 [M + H].sup.+ 183 ##STR00380## B Mass
spectrum (ESI.sup.+): m/z = 397 [M + H].sup.+ 184 ##STR00381## B
Mass spectrum (ESI.sup.+): m/z = 378 [M + H].sup.+ 185 ##STR00382##
J Mass spectrum (ESI.sup.+): m/z = 467 [M + H].sup.+ 186
##STR00383## B -- 187 ##STR00384## H Mass spectrum (ESI.sup.+): m/z
= 370 [M + H].sup.+ 188 ##STR00385## B Mass spectrum (ESI.sup.+):
m/z = 427 [M + H].sup.+ 189 ##STR00386## B Mass spectrum
(ESI.sup.+): m/z = 475 [M + H].sup.+ 190 ##STR00387## B Mass
spectrum (ESI.sup.+): m/z = 431 [M + H].sup.+ 191 ##STR00388## B
Mass spectrum (ESI.sup.+): m/z = 453 [M + H].sup.+ 192 ##STR00389##
J Mass spectrum (ESI.sup.+): m/z = 517/519 (Cl) [M + H].sup.+ 193
##STR00390## B Mass spectrum (ESI.sup.+): m/z = 384 [M + H].sup.+
194 ##STR00391## B Mass spectrum (ESI.sup.+): m/z = 384 [M +
H].sup.+ 195 ##STR00392## P Mass spectrum (ESI.sup.+): m/z = 384 [M
+ H].sup.+ 196 ##STR00393## P Mass spectrum (ESI.sup.+): m/z = 384
[M + H].sup.+ 197 ##STR00394## Q Mass spectrum (ESI.sup.+): m/z =
356 [M + H].sup.+ 198 ##STR00395## B Mass spectrum (ESI.sup.+): m/z
= 384 [M + H].sup.+ 199 ##STR00396## B Mass spectrum (ESI.sup.+):
m/z = 340 [M + H].sup.+ 200 ##STR00397## B Mass spectrum
(ESI.sup.+): m/z = 394 [M + H].sup.+ 201 ##STR00398## B Mass
spectrum (ESI.sup.+): m/z = 394 [M + H].sup.+ 202 ##STR00399## P
Mass spectrum (ESI.sup.+): m/z = 384 [M + H].sup.+ 203 ##STR00400##
R Mass spectrum (ESI.sup.+): m/z = 410 [M + H].sup.+ 204
##STR00401## Q Mass spectrum (ESI.sup.+): m/z = 356 [M + H].sup.+
205 ##STR00402## Q Mass spectrum (ESI.sup.+): m/z = 356 [M +
H].sup.+ 206 ##STR00403## P Mass spectrum (ESI.sup.+): m/z = 356 [M
+ H].sup.+ 207 ##STR00404## P Mass spectrum (ESI.sup.+): m/z = 356
[M + H].sup.+ 208 ##STR00405## B Mass spectrum (ESI.sup.+): m/z =
368 [M + H].sup.+
[0696] The following compounds are also prepared analogously to the
above-mentioned Examples and other methods known from the
literature:
TABLE-US-00005 In analogy to Example No. Chemical
Name/Structure/Remarks Procedure 209 ##STR00406## B 210
##STR00407## B 211 ##STR00408## B 212 ##STR00409## B 213
##STR00410## B 214 ##STR00411## B 215 ##STR00412## B 216
##STR00413## B 217 ##STR00414## B 218 ##STR00415## B 219
##STR00416## B 220 ##STR00417## B 221 ##STR00418## B 222
##STR00419## Procedure B followed by reduction with NaBH.sub.4 in
EtOH at room temperature 223 ##STR00420## B 224 ##STR00421## B 225
##STR00422## B 226 ##STR00423## B 227 ##STR00424## B 228
##STR00425## B 229 ##STR00426## B 230 ##STR00427## B 231
##STR00428## B 232 ##STR00429## B 233 ##STR00430## B 234
##STR00431## B 235 ##STR00432## B 236 ##STR00433## B 237
##STR00434## B 238 ##STR00435## B 239 ##STR00436## B 240
##STR00437## Procedure B followed by reduction with NaBH.sub.4 in
EtOH at room temperature 241 ##STR00438## B 242 ##STR00439## B 243
##STR00440## B 244 ##STR00441## B 245 ##STR00442## B 246
##STR00443## G 247 ##STR00444## B 248 ##STR00445## B 249
##STR00446## B 250 ##STR00447## from Example 249 with
(F.sub.3CO).sub.2O, iPr.sub.2NEt in CH.sub.2Cl.sub.2 at room
temperature and subsequent treatment with NaOH in MeOH 251
##STR00448## from compound Example 212 employing the conditions
described in Example LVI 252 ##STR00449## B 253 ##STR00450## B 254
##STR00451## B 255 ##STR00452## B 256 ##STR00453## B 257
##STR00454## B 258 ##STR00455## B 259 ##STR00456## B 260
##STR00457## B 261 ##STR00458## B 262 ##STR00459## B 263
##STR00460## B 264 ##STR00461## B
[0697] Some examples of formulations will now be described in which
the term "active substance" denotes one or more compounds according
to the invention, including the salts thereof. In the case of one
of the combinations with one or additional active substances as
described previously, the term "active substance" also includes the
additional active substances.
Example A
Tablets Containing 100 mg of Active Substance
Composition:
TABLE-US-00006 [0698] 1 tablet contains: active substance 100.0 mg
lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg
magnesium stearate 2.0 mg 220.0 mg
Method of Preparation:
[0699] The active substance, lactose and starch are mixed together
and uniformly moistened with an aqueous solution of the
polyvinylpyrrolidone. After the moist composition has been screened
(2.0 mm mesh size) and dried in a rack-type drier at 50.degree. C.
it is screened again (1.5 mm mesh size) and the lubricant is added.
The finished mixture is compressed to form tablets. [0700] Weight
of tablet: 220 mg [0701] Diameter: 10 mm, biplanar, facetted on
both sides and notched on one side.
Example B
Tablets Containing 150 mg of Active Substance
Composition:
TABLE-US-00007 [0702] 1 tablet contains: active substance 150.0 mg
powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0
mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0
mg
Preparation:
[0703] The active substance mixed with lactose, corn starch and
silica is moistened with a 20% aqueous polyvinylpyrrolidone
solution and passed through a screen with a mesh size of 1.5 mm.
The granules, dried at 45.degree. C., are passed through the same
screen again and mixed with the specified amount of magnesium
stearate. Tablets are pressed from the mixture. [0704] Weight of
tablet: 300 mg [0705] die: 10 mm, flat
Example C
Hard Gelatine Capsules Containing 150 mg of Active Substance
Composition:
TABLE-US-00008 [0706] 1 capsule contains: active substance 150.0 mg
corn starch (dried) approx. 180.0 mg lactose (powdered) approx.
87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg
Preparation:
[0707] The active substance is mixed with the excipients, passed
through a screen with a mesh size of 0.75 mm and homogeneously
mixed using a suitable apparatus. The finished mixture is packed
into size 1 hard gelatine capsules. [0708] Capsule filling: approx.
320 mg [0709] Capsule shell: size 1 hard gelatine capsule.
Example D
Suppositories Containing 150 mg of Active Substance
Composition:
TABLE-US-00009 [0710] 1 suppository contains: active substance
150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000
460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0
mg
Preparation:
[0711] After the suppository mass has been melted the active
substance is homogeneously distributed therein and the melt is
poured into chilled moulds.
Example E
Ampoules Containing 10 mg Active Substance
Composition:
TABLE-US-00010 [0712] active substance 10.0 mg 0.01N hydrochloric
acid q.s. double-distilled water ad 2.0 mL
Preparation:
[0713] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 2 mL ampoules.
Example F
Ampoules Containing 50 mg of Active Substance
Composition:
TABLE-US-00011 [0714] active substance 50.0 mg 0.01N hydrochloric
acid q.s. double-distilled water ad 10.0 mL
Preparation:
[0715] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 10 mL ampoules.
* * * * *